6048 results for "canc*"

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• Cell-free DNA TAPS for early cancer detection

  Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

  Study EGAS00001004962

• Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

  Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data, we applied non-negative matrix factorization, which identified four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed signature (SCLC-A, N, P and I, respectively). The presence of these subtypes were then validated in tumor gene expression data from the IMpower133 clinical trial.

  Study EGAS00001004888

• Detection and characterization of lung cancer using cell-free DNA fragmentomes

  Lung cancer remains the leading cause of cancer death world-wide, largely due to its late diagnosis. Non-invasive approaches for assessment of cell-free DNA (cfDNA) provide an opportunity for detection and intervention that may have broader accessibility than current imaging approaches. Using a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation, we examined a prospective study of 365 individuals at risk for lung cancer (Lung Cancer Diagnostic Study, LUCAS), including 129 individuals ultimately diagnosed with lung cancer and 236 individuals determined to not have lung cancer. We externally validated the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 predominantly early stage lung cancer patients. Combining fragmentation features with clinical risk factors and CEA levels followed by CT imaging detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites could be used to distinguish individuals with small cell lung cancer (SCLC) from those with non-small cell lung cancer (NSCLC) with high accuracy (AUC=0.98). Among individuals with lung cancer, a higher cfDNA fragmentation score was associated with tumor size and invasion, and represented an independent prognostic indicator of survival. These studies provide a facile approach for non-invasive detection of lung cancer and clinical management of this disease.

  Study EGAS00001005340

• PanCuRx Translational Research Initiative

  The goal of the PanCuRx TRI is to seek solutions to the high fatality rate of pancreatic adenocarcinoma (PDAC), the most common type of pancreatic cancer, by generating new knowledge about the genetics and biology of the disease, mechanisms of how tumours grow and tailored treatment options. PDAC is the fourth leading cause of cancer death in Canada and is expected to become the second-leading cause of cancer death within the next decade. The current five-year survival rate of eight per cent is the lowest of all epithelial cancers. There are major clinical challenges to treating the disease, including the fact that PDAC spreads to other parts of the body early so surgical removal of the tumour benefits few patients, that PDAC has proven relatively resistant to systemic therapies such as chemotherapy and that there has been limited benefit from the use of newer molecular targeted agents. The PanCuRx team has created the world’s first resource of tumour-purified PDAC whole genomes; more than 500 PDAC samples, with combined clinical annotation, have been successfully sequenced and analyzed at the Ontario Institute for Cancer research in Toronto. The resulting clinical genomic resource created from this data has led to multiple new findings that have established a framework to better understand PDAC biology and lays the foundation for new genomic approaches to better understanding the disease. The team also launched a clinical trial called COMPASS (Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection: A Prospective Study), which is recruiting patients with advanced PDAC (both locally advanced and metastatic) at The Princess Margaret Cancer Centre (PM) in Toronto. The study uses the molecular results from individual patient tumours to guide selection of better second line treatment on a case-by-case basis. The primary objective of the initial study was to assess the feasibility of collecting tumour materials from patients with advanced PDAC and delivering results within 56 days of biopsy. Having achieved this objective, the trial has expanded to other cancer centres across Canada. Pancreatic cancer is one of the most deadly forms of cancer and outcomes have not improved in four decades. The PanCuRx initiative is providing a better understanding of the disease and actively applying new knowledge to cancer patients through clinical trials. This knowledge will help to improve quality of life and prolong survival for pancreatic cancer patients worldwide.

  Study EGAS00001002543

• TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

  We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

  Study EGAS00001002556

• Immune induction strategies to enhance the sensitivity to PD-1 blockade in metastatic triple negative breast cancer: the TONIC-trial

  The response rate in metastatic triple negative breast cancer (TNBC) to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. In the first stage of this adaptive, non-comparative phase II trial (TONIC-trial; NCT02499367), 67 patients with metastatic TNBC were randomized to nivolumab without induction or to one of four induction treatments, consisting of irradiation of one metastatic lesion (3x8 Gy) or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by nivolumab. In the overall cohort of 66 evaluable patients, the objective response rate (ORR; iRECIST16) was 20% (95% CI: 11%-31%), with two complete responses and 11 partial responses. The majority of clinical responses were observed on nivolumab in the cisplatin (ORR 23%; 3/13) and doxorubicin (ORR 35%; 6/17) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the clinical and translational data of this study testing different immune induction strategies prior to nivolumab suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant further confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

  Study EGAS00001003535

• Single-cell analysis for metastatic gastric adenocarcinoma

  Intra-tumoral heterogeneity (ITH) is the fundamental property of cancer, however, the origins of ITH remain poorly understood. Here we performed single-cell RNA sequencing of peritoneal carcinomatosis (PC) from patients with advanced gastric adenocarcinoma (GAC), constructed a transcriptome map of 45,048 PC cells, profiled the transcriptome states of diverse tumor cell lineages and types, incisively explored ITH of PC tumor cells, and identified significant correlates with patient survival.

  Study EGAS00001004443

• The aim of this project is to identify, on 15 French Caucasian and 10 African-Caribbean men, through an integrative approach of DNA sequencing and transciptomic analyses, relevant genomic events that characterize or allow targeting the various phenotypes of aggressiveness of early stages of prostate cancer.

  Every year about 70,000 new cases of prostate cancer are diagnosed in France and 8,700 men died from this disease. But the incidence and the rate of mortality per 100,000 men in the French West Indies are respectively 1.5x and 2x upper than the rates observed in the metropolitan France. The aim of this project is to identify, on 15 French Caucasian and 10 African-Caribbean men, through an integrative approach of DNA sequencing and transciptomic analyses, relevant genomic events that characterize or allow targeting the various phenotypes of aggressiveness of early stages of prostate cancer.

  Study EGAS00001002176

• Canadian prostate cancer samples (CPC-GENE) for PanProstate study

  CPC-GENE has sequenced the genomes of 350 intermediate risk prostate cancers to identify genetic signatures that differ in cancers that responded well to treatment compared with those that did not. CPC-GENE also has sequenced multiple regions of prostate cancer from the same gland to determine if and how the genetic make-up of prostate cancer varies within an individual man’s prostate

  Study EGAS00001003037

• Genomic analysis of high-risk prostate cancer.

  Whole genome sequencing analysis of high risk localised primary prostate cancer samples including metastatic samples was performed across 153 tumour samples with matching germline sequencing (whole blood). Samples were all fresh frozen frozen section confirmed tumour specimens and associated clinical and pathological metadata is available for these specimens.

  Study EGAS00001003088

• PanProstate Cancer Group UK data

  THE PAN PROSTATE CANCER PROJECT: Many groups around the world have generated Whole Genome DNA Sequence (WGS) data from prostate cancer patients. The pan prostate group have gathered with the idea that the accumulated data, should be collected and compared in a common format including common storage, re-analysis through a single pipeline, and investigation to achieve a variety of scientific goals. The combined collection would include the following categories: (i) cancers from different ethnic groups: eg Caucasian, Asian, Black Caribbean; (ii) cancer from different stages of progression from normal, to organ-confined disease, to metastases; (iii) early-onset prostate cancer; (iv) prostate cancer from aggressive and indolent disease; and (v) prostate cancer patients managed by different treatments with information linked to long-term clinical follow up data in many cases.This study contains the initial pilot samples (train 1) from the CRUK-ICGC prostate group.

  Study EGAS00001002876

• TRACERx 100: whole exome data of the first 100 TRACERx tumours

  BACKGROUNDTRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC). METHODSMultiregion high-depth whole-exome sequencing (M-seq) was performed on 100 early stage NSCLC tumors resected prior to systemic therapy. A total of 327 tumor regions were sequenced and analyzed to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between ITH and recurrence-free survival (RFS). RESULTSWidespread ITH was observed for both somatic copy number alterations (median 48% [0.03-88%]) and mutations (median 30% [0.5-93%]). Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal. However, heterogeneous driver alterations occurring later in evolution were found in over 75% of tumors and were common in PIK3CA, NF1 and genes involved in chromatin modification and DNA response and repair. Genome doubling and ongoing dynamic chromosomal instability (CIN), illustrated by mirrored subclonal allelic imbalance, were identified as causes of ITH resulting in parallel evolution of driver copy number events, including amplifications of CDK4, FOXA1, and BCL11A. Elevated copy number heterogeneity was associated with shorter RFS (HR=4.9, P=0.00044), which remained significant in a multivariate analysis.CONCLUSIONSITH mediated through CIN, rather than point mutational heterogeneity, was associated with increased risk of relapse, supporting its value as a prognostic predictor, and the need to target this high-risk phenotype.

  Study EGAS00001002247

• Psoriatic_arthritis

  This is a pilot single cell mRNA sequencing experiment to study immune cells in psoriatic arthritis.

  Study EGAS00001002104

• Tracing early predictors of glioma evolution under therapy

  Clonal evolution drives cancer progression and therapeutic resistance. Recent studies revealed divergent longitudinal trajectories in gliomas, but early molecular traits steering post-treatment cancer evolution remain unclear. We analyzed sequencing data of 544 initial-recurrent adult diffuse glioma pairs to identify genomic and transcriptomic early predictors of tumor evolution in each molecular subtype.

  Study EGAS00001006894

• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• NCTN: A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (S0819)

  Study ID: S0819NCT Number: NCT00946712 SWOG Cancer Research NetworkSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) (S0819)Trial Description: This randomized phase III trial studies carboplatin and paclitaxel to compare how well they work with or without bevacizumab and/or cetuximab in treating patients with stage IV or non-small cell lung cancer that has returned after a period of improvement (recurrent). Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may prevent the growth of new blood vessels that tumor needs to grow. Cetuximab may also stop cancer cells from growing by binding and interfering with a protein on the surface of the tumor cell that is needed for tumor growth. It is not yet known whether giving carboplatin and paclitaxel are more effective with or without bevacizumab and/or cetuximab in treating patients with non-small cell lung cancer. Clinical data presented in the following publication(s):PMID 29169877Disease type(s): Lung, Mediastinal and Pleural Neoplasm - Non-Small Cell Lung CancerClinical Dataset(s) included:NCT00946712-D1 (PMID 29169877): There are three datasets associated with PMID 29169877: NCT00946712-D1, -D2, and -D3. This clinical dataset, NCT00946712-D1, contains patient-level data (one row per patient), including eligibility, evaluability, treatment, demographic, EGFR FISH results, protocol deviations, and baseline information. It also contains response and survival data.NCT00946712-D2 (PMID 29169877): There are three datasets associated with PMID 29169877: NCT00946712-D1, -D2, and -D3. This toxicity dataset, NCT00946712-D2, contains event-level information (one row per patient per adverse event experienced on trial).NCT00946712-D3 (PMID 29169877): There are three datasets associated with PMID 29169877: NCT00946712-D1, -D2, and -D3. This dataset, NCT00946712-D3, contains specific reasons for off treatment due to toxicity.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004231

• Atezolizumab Plus Personalized Neoantigen Vaccination in Patients with Urothelial Cancer: a Phase 1 Trial

  This is a phase 1 single center clinical trial evaluating a multi-peptide personalized neoantigen vaccine, PGV001, in combination with atezolizumab for patients with urothelial cancer. Patients were enrolled in either the adjuvant or metastatic setting. Those in the adjuvant setting included patients considered high risk of recurrence (pathological stage ypT2-T4 or ypN+ for those treated with prior neoadjuvant chemotherapy or pT3-T4 or pN+ for those not treated with prior neoadjuvant chemotherapy). Those in the metastatic setting included patients progressing after prior chemotherapy or those with at least stable disease after chemotherapy treated as “switch maintenance” therapy. The primary endpoint was feasibility (including the number of neoantigens identified per patient, vaccine production time, the proportion of patients consenting to the vaccine development phase for whom a vaccine product was prepared, and the proportion of patients eligible for the treatment phase who completed the priming cycle 1 of PGV001 plus atezolizumab) and safety. Secondary endpoints included the objective response rate, progression-free survival or disease-free survival, overall survival, and immunomodulatory effects of treatment. Urothelial tumor tissue and normal tissue or peripheral blood specimens were utilized for DNA sequencing. HLA typing was performed utilizing genomic DNA isolated from whole blood, and RNA sequencing was performed utilizing tumor tissue specimens. Neoantigen prediction and final selection for incorporation into the vaccine was determined by the OpenVax computational pipeline. 12 patients were initially enrolled into the vaccine development phase and 10 patients initiated the treatment phase. PGV001 was administered with poly-ICLC and tetanus peptide on subsequent days for up to 10 doses, including an initial priming cycle 1. Atezolizumab was administered every 3 weeks for up to 1 year in the adjuvant setting or 2 years in the metastatic setting. The vaccine was feasible and safe, the median vaccine production time was 20.3 weeks, and 100% of patients that initiated the treatment phase completed the priming cycle. The most common treatment-related adverse events were local grade 1 injection site reactions, fever, and fatigue. Three of the 4 patients in the adjuvant setting remained disease-free at median follow-up of 39.5 months. There was a 40% objective response rate among patients with measurable disease in the metastatic setting. The single patient treated as “switch maintenance” therapy remained with no evidence of disease at 39.4 month follow-up. All patients demonstrated on-treatment neoantigen-specific T cell reactivity, as measured by ELISPOT and flow cytometry assays. Overall, PGV001 plus atezolizumab was feasible, safe, and warrants further investigation. Whole exome sequencing from tumor tissue and normal tissue or whole blood specimens and RNA sequencing from tumor tissue specimens will be available through dbGaP.

  Study phs003922

• Somatic Mutations in Individual Skin Cells

  Ultraviolet (UV) radiation is the primary cause of melanoma through the acquisition of driver mutations in melanocytes. It also plays a significant role in oncogenesis in other skin cells, such as keratinocytes. However, the mutational profiles vary widely among different skin cancers, and the early mutational processes in different cell types from the same skin, is not well understood. Additionally, our preliminary studies also suggest that the mutation burden in different skin cells vary significantly based on risk factors such as the anatomical site and the use of tanning beds. To explore this, we employed innovative Next Generation Sequencing (NGS) tools to perform a site-matched comparison of the genomic landscapes of melanocytes, keratinocytes, and fibroblasts. From 20 biopsies of physiologically normal skin, collected from various anatomical sites across 16 donors, we have performed DNA-sequencing on 106 melanocytes, 78 keratinocytes and 13 fibroblasts. Of these samples, we have also simultaneously performed RNA-sequencing on 78 melanocytes, 46 keratinocytes and 9 fibroblasts. For normal bulk DNA, we also performed targeted (UCSF500; n=9) or exome sequencing (n=8) of skin or saliva samples from the donors.

  Study phs003683

• Transcriptome of Human Merkel Cell Carcinoma

  Merkel Cell Carcinoma (MCC) is a rare and aggressive skin cancer with poorly understood molecular characteristics. In this study, we conducted RNA sequencing (RNA-Seq) on tumor samples from 9 human MCC patients to unravel the intricate transcriptional landscape of MCC. Data available in dbGaP include bulk RNA sequencing of 9 tumor samples.

  Study phs003411

• Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Orthotopic CNS Tumors

  The goal of this project is to advance the development of effective therapies for pediatric brain cancers through preclinical in vivo testing of novel agents. We utilize a well-characterized panel of approximately 150 patient-derived orthotopic xenograft (PDOX) models that replicate the histopathologic and molecular features of the original patient tumors. These models represent multiple pediatric CNS tumor types, including high-grade glioma, medulloblastoma, ependymoma, diffuse intrinsic pontine glioma (DIPG), and atypical teratoid/rhabdoid tumor (ATRT), across diverse disease stages and molecular subtypes. As part of this effort, the PDOX models are being molecularly characterized to identify promising therapeutic candidates. Molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Demographic and clinical data (e.g., diagnosis, disease site, disease status) are also shared.

  Study phs003162

• Kids First: Childhood Cancer Data Initiative (CCDI) - Discovering the Timing and Origins of Bone and Soft Tissue Cancers

  Sarcoma are cancers of bone and connective tissue that disproportionately affect children and are often difficult to diagnose. This study presents the genome and transcriptome sequences of carefully curated sarcoma tumors and matched non-neoplastic (normal) specimens including a cohort of benign bone and soft tissue tumors, totalling 1122 sequences from 310 participants, covering 69 various subtypes. High-quality pathology reviewed specimens (FF or FFPE) with detailed clinical data were selected to inform key temporal landmark in sarcoma development – from tumor initiation to the generation of critical oncogenic fusions and malignant potential, to possible relapse or metastasis.

  Study phs002827

• NCTN: Treatment for Very Low and Standard Risk Favorable Histology Wilms Tumor (AREN0532)

  Study ID: AREN0532NCT Numbers: NCT00352534Children's Oncology GroupSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Treatment for Very Low and Standard Risk Favorable Histology Wilms Tumor (AREN0532)Trial Description: This phase III trial is studying vincristine, dactinomycin, and doxorubicin with or without radiation therapy or observation only to see how well they work in treating patients undergoing surgery for newly diagnosed stage I, stage II, or stage III Wilms' tumor. Drugs used in chemotherapy, such as vincristine, dactinomycin, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving these treatments after surgery may kill any tumor cells that remain after surgery. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient.Clinical data presented in the following publication(s):PMID 27811504PMID 29211618Disease type(s): Kidney Neoplasm - Wilms TumorClinical Dataset(s) included:NCT00352534-D1 (PMID 27811504): There is one dataset (-D1) for the AREN0532 primary publication 27811504, reporting on the trial's very low-risk cohort. This dataset contains baseline characteristics, WT1 mutation status, loss of heterozygosity, relapse sites, presence of intralobar and perilobar rests, survival, secondary malignancy, and radiotherapy type data.NCT00352534-D2 (PMID 29211618): There are two datasets (-D2 and -D3) for the AREN0532 primary publication 29211618, reporting on patients with stage III favorable-histology Wilms tumor. There is one row for each patient enrolled. The dataset contains the data for the consort flow of patient enrollment, baseline characteristics, surgery details, 1p/16q loss of heterozygosity status, second malignant neoplasm, survival, relapse site, grade of adverse events, and tumor status data for the patients on AREN0532 as reported in the manuscript.NCT00352534-D3 (PMID 29211618): There are two datasets (-D2 and -D3) for the AREN0532 primary publication 29211618, reporting on patients with stage III favorable-histology Wilms tumor. This dataset contains EFS and OS data for patients enrolled on the Q9401 study described in the manuscript to compare outcomes for patients on AREN0532 to similar patients on Q9401 who received the same therapy.Select data from Q9401 (NCT00002611) used in AREN0532 publication PMID 29211618 are contained in NCT003525234-D3.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004139

• Genomic Characterization CS-MATCH-0007 Arm C1

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm C1 is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with MET amplification are treated with Crizotinib. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002177

• MP2PRT: PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG HN002 and RTOG 1016

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network. This study, titled “PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG-HN002 and RTOG 1016”, is one of the selected studies under this program. For this study, molecular characterization (i.e., WES, Total RNAseq, and multiplex immunofluorescence staining) was performed on formalin-fixed paraffin embedded tumor tissue and matching germline previously collected from patients with HPV-related oropharyngeal cancer. This project will investigate genomic alterations within the PI3K pathway (PIK3CA and PTEN). It is hypothesized that an improved understanding of this pathway in a specific genetic context may lead to the development of novel therapies to guide future clinical trials and improve the clinical outcomes of patients with HPV-positive oropharyngeal cancer.

  Study phs003089

• Analysis of Epigenomes and Genome Topology in Colorectal Cancer

  When diagnosing cancer, pathologists use nuclear morphology as a hallmark of tumor cells, but the topological changes linked to alterations in the shape of the nucleus were poorly understood. To uncover the molecular changes that occur in the 3D structure of cancer genomes, we integrated topological maps for colon tumors and normal colon tissues with epigenetic, transcriptional, and imaging data. We characterized tumor-associated changes in chromatin loops, topologically associated domains (TADs), and large-scale compartments. We found that chromatin loop rewiring contributes to oncogenic gene expression programs. Whereas TAD structures are largely stable, the spatial partitioning of the open and closed genome compartments is compromised in tumors and is accompanied by hypomethylation and histone mark rearrangements. We also identified a compartment that is reorganized in tumors and is at the interface between the canonical A and B compartments. Similar changes were evident in non-malignant cells that had accumulated excessive cellular divisions. Our analyses suggest that these compartment changes repress stemness and invasion programs while inducing immunity genes, and they may therefore restrain malignant progression.

  Study phs002288

• NCTN: A Randomized Phase III Post-operative Trial of Platinum Based Chemotherapy vs. Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer following Neoadjuvant Chemotherapy (EA1131)

  Study ID: EA1131 NCT Number: NCT02445391 ECOG-ACRIN Cancer Research Group Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: A Randomized Phase III Post-operative Trial of Platinum Based Chemotherapy vs. Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer following Neoadjuvant Chemotherapy (EA1131) Trial Description: This randomized phase III trial studies how well cisplatin or carboplatin (platinum based chemotherapy) works compared to capecitabine in treating patients with remaining (residual) basal-like triple-negative breast cancer following chemotherapy after surgery (neoadjuvant). Drugs used in chemotherapy, such as cisplatin, carboplatin and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cisplatin or carboplatin is more effective than capecitabine in treating patients with residual triple negative basal-like breast cancer. Clinical data presented in the following publication(s): PMID 34092112 Disease type(s): Breast Neoplasm - Breast Cancer - Invasive Clinical dataset(s) included: NCT02445391-D1 (PMID 34092112): There are three datasets for PMID 34092112. This dataset, NCT02445391-D1, contains baseline characteristics, stratification factors, treatment, second primary cancer, cause of death and efficacy data. The data reflect the study database as of April 7, 2021. All patients who were randomized to one of the three arms were included in the database (NCT02445391-D1). Accrual was open to arm A (observation) and arm B (platinum) prior to Amendment #3, and accrual to arm A was permanently closed and accrual to arm C (capecitabine) was opened in Amendment #3. NCT02445391-D2 (PMID 34092112): There are three datasets for PMID 34092112. This dataset, NCT02445391-D2 contains data on dose modification. The data reflect the study database as of April 7, 2021. NCT02445391-D3 (PMID 34092112): There are three datasets for PMID 34092112. This dataset, NCT02445391-D3, contains toxicity data. The data reflect the study database as of April 7, 2021. All treatment-related AEs were included in the database, and only the worst degree was reported in the paper. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004236

• Long-Read Sequencing of Ovarian Cancer Organoids

  Two patient-derived organoids were derived from separate ascites fluid collections from a patient diagnosed with high-grade mullerian carcinoma, that could not be confidently subclassified based on the limited specimen. Long-read sequencing whole genome sequencing (WGS) was performed on the organoids, OC104 and OC109, using the Oxford Nanopore Technologies PromethION24 with V14 ligation kit. Information from genomic findings and further pathology on organoids suggests refining the diagnosis to mucinous ovarian carcinoma.

  Study phs004795

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program – Sarcomas and other Solid Tumors

  The primary goal of this project involves the comprehensive molecular profiling of patient-derived xenograft (PDX) mouse tumor models. Molecular profiling of each PDX model will include whole exome sequencing (WES), RNAseq, MethylEPIC arrays, CytoSNP array, and DNA fingerprint for quality control. Limited clinical demographic data (e.g. diagnosis, disease site, disease status) will be obtained. This data can be utilized to validate PDX models with matched patient tumors and can be used to guide model selection for downstream preclinical drug testing.

  Study phs003161

• Childhood Cancer Data Initiative (CCDI): Integrating Longitudinal Clinical, Sociodemographic and Genomic Data into the NCCR

  The goal of this study is to contribute clinical and genomic data from a large institutional cohort of pediatric cancer patients who had tumor genomic profiling between 2013 and 2019 at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center. Clinical data include demographics, diagnosis (classified according to the International Classification of Diseases for Oncology (ICD-O-3.2), stage, and biospecimen associated data. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel of up to 447 cancer genes for detection of single-nucleotide variants (SNV), insertions, and deletions, and copy number alterations (CNA), as well as selected intronic regions for up to 60 genes for the detection of structural variants (SV). This dataset includes a patient and sample identifier (GENIE ID) that can be used to link the genomic data included in this dataset to additional longitudinal clinical cancer data on a subset of patients that was submitted to the National Childhood Cancer Registry (NCCR).

  Study phs002677

• Whole Exome and RNA Sequencing of 22 Patient-Derived Xenografts from Estrogen Receptor-Positive Breast Cancers

  We performed RNA and whole exome sequencing on 22 patient-derived xenografts (PDX) from estrogen receptor-positive (ER+) breast cancers, in the presence and absence of estradiol (E2) supplementation. Exome coverage across more than 3,500 clinically relevant genes that previously were covered below 20X (~2.72Mb) was achieved. On average, 11.2Gb of unique sequence data were generated with 95.3% of the bases in the exome design covered to 20x read depth or greater. RNA sequencing was generated from xenograft tumors. Between 50 and 85M total reads were performed. The average strand-specificity and rRNA rate was 98% and 1.5%, respectively. Transcripts for 17,000 to 27,087 genes were detected in these samples.

  Study phs003324

• NCTN: Randomized Phase III Study of Maintenance Therapy With Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC (E5508)

  Study ID: E5508NCT Number: NCT01107626ECOG-ACRIN Cancer Research Group Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC (E5508) Trial Description: RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer. Clinical data presented in the following publication(s): PMID 31361535 Disease type(s): Lung, Mediastinal and Pleural Neoplasm - Non-Small Cell Lung Cancer Clinical dataset(s) included: NCT01107626-D1 (PMID 31361535): There are two different datasets for PMID 31361535 from trial E5508. This dataset, NCT01107626-D1, contains baseline characteristics, treatment assignment, prior treatment, metastatic sites and efficacy data. Pemetrexed or bevacizumab is used for maintenance therapy of advanced no squamous non-small cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. This study contains two step registration, induction therapy step and maintenance therapy. All patients who were registered to at least one of the steps are included. Due to data cleaning efforts, data may contain slight discrepancies from that reported in Table 1 and Table 2 in the publication (PMID 31361535). The number of each metastatic site is incorrect in the publication: The data in this dataset is correct.NCT01107626-D2 (PMID 31361535): There are two different datasets for PMID 31361535 from trial E5508. This dataset, NCT01107626-D2, contains toxicity data. Pemetrexed or bevacizumab is used for maintenance therapy of advanced no squamous non‐small cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. This study contains two step registration, induction therapy step and maintenance therapy. All patients who were registered to at least one of the steps are included.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004240

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Oral Squamous Cell Carcinoma in Taiwan

  Oral cavity squamous cell carcinoma (OSCC) is the major subtype (~90%) of oral cancer, which is leading cancer with high mortality worldwide. The environmental risk factors associated with OSCC are quite different in Taiwan as compared to other populations. In most non-Taiwanese populations, OSCC is often associated with tobacco chewing, cigarette smoking, alcohol drinking, or human papillomavirus (HPV) infection. In Taiwan, in contrast, the OSCC occurs mainly in males aged 30 years or older who have habitual betel nut chewing, cigarette smoking, and alcohol drinking. To uncover molecular mechanisms and identify new therapeutic strategies of oral squamous cell carcinoma, this study recruited 112 treatment-naïve OSCC patients and generated multi-omics data, including WES, RNA-Seq, TMT-labeled proteomes, and phosphoproteomes from paired normal/tumor tissues. We have investigated our multi-omics data, covering molecular characterizations such as mutation signatures, impacts of mutations on RNA/protein/phosphoprotein, RNA-protein correlation, somatic copy number alteration, and the relationship with RNA & protein, proteome, and phosphoproteome analysis (T vs NAT), novel peptides (somatic variants, neoantigens, CT antigens, T cell receptors, etc.), as well as molecular subtyping (& pathway analysis). Notably, we have discovered a higher frequency of APOBEC3B deletion polymorphism in the Taiwanese population, and APOBEC3A is a potential prognostic biomarker. Our proteogenomic data enable us to further stratify patients into four groups based on APOBE3A expression level, which is found inversely correlated with EGFR expression. Therefore, the patients with high EGFR and low APOBEC3A expression may benefit from anti-EGFR therapy, while those with low EGFR and high APOBEC3A expression may benefit from immunotherapy. To clarify if there is an interaction between genetic polymorphisms and betel nut chewing habit in Taiwanese OSCC, we plan to concurrently evaluate the effect of habitual betel nut chewing on the gene mutation pattern, the dysregulated protein/phosphoproteins as novel biomarkers and/or therapeutic targets, and the molecular subtyping of patients for effective treatments. 

  Study phs002580

• Evolution of Structural Rearrangements in Prostate Cancer Intracranial Metastases

  Intracranial metastases in prostate cancer are uncommon but clinically aggressive. We sought to characterize prostate cancer intracranial metastases in order to improve our understanding of their pathogenesis and to promote the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) on samples from 21 patients. The WGS samples include 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n=6) and non-brain prostate cancer metastases (n=26).

  Study phs003357

• Genetic Factors Associated with Anthracycline-Induced Cardiomyopathy (COG-ALTE03N1)

  We investigated the genetic mechanisms underlying anthracycline-induced cardiomyopathy, a serious long-term complication among childhood cancer survivors. We focused on the role of DNA damage response and repair (DDR) genes, which had not been previously studied in this context. A gene-based and pathway-based approach was applied to assess both the main effects and gene-by-anthracycline interaction effects of DDR genes on cardiomyopathy risk. The analysis was conducted using a matched case-control design within the COG-ALTE03N1 study, including 113 cases and 226 controls, all of whom were non-Hispanic White childhood cancer survivors exposed to anthracyclines. For each case, we randomly selected 1-3 childhood cancer survivors with no cardiomyopathy, matched on primary cancer diagnosis, year of diagnosis (±10y), and race/ethnicity. The selected controls had to have a longer duration of follow-up compared with time from cancer diagnosis to cardiomyopathy for the corresponding case. Participants provided blood or saliva for germline DNA isolation and genotyping. Genotyping was performed using Illumina HumanOmniExpress-12 v1.0 (709,358 SNPs) and IlluminaOmni5Exome-4 v1.3 arrays (4,293,368 SNPs), with merging of genotype data from the two arrays (683,781 overlapped SNPs) and quality control (QC) using PLINK. Of the 220 genes in the MD Anderson DDR gene website, 187 genes with 2,220 single nucleotide polymorphisms [SNPs] identified on our array data were included in the analyses. A total of 2,170 SNPs were retained in the final gene-based and pathway-based analysis in 339 anthracycline-exposed non-Hispanic White (NHW) patients (113 cases; 226 controls). Key findings included significant associations for FANCC and XRCC5 with cardiomyopathy risk (main effect), and a significant gene-environment interaction involving MGMT. The study also confirmed the involvement of DDR-related biological pathways through both genetic association and interaction analyses.Data Available Through dbGaP: • Genotype data (GWAS) for all study participants • Phenotype data: age at primary cancer diagnosis, sex, race/ethnicity, case-control status This dataset supports further research into genetic susceptibility to chemotherapy-induced adverse outcomes and enables cross-cohort comparisons in cardio-oncology.

  Study phs003792

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• Proteogenomic Characterization Unveils Biomarkers Associated With Chemoresistance in Muscle Invasive Bladder Cancer

  Cisplatin-based neoadjuvant chemotherapy (NAC) combined with radical cystectomy has been used as a standard of care for patients with clinically non-metastatic muscle invasive urothelial bladder cancer, but 40-50% patients will benefit from the treatment. Molecular subtypes of muscle invasive bladder cancer (MIBC) provide a possible biomarker roadmap that may help identify patients who may or may not respond to NAC. Recently, by integrating Mass Spectrometry-based proteomics, proteogenomic studies from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) have demonstrated the potential of this approach in prioritizing candidate driver genes and facilitating understanding of the chemotherapy resistance mechanisms. To demonstrate the proteogenomic workflow for investigating the mechanisms underlying chemotherapy resistance in MIBC, we conducted proteogenomic characterization of 46 pre- and 14 post- treatment tumors, including whole exome sequencing (WES), mRNA sequencing, Tandem Mass Tag (TMT)-proteomics, or TMT-phosphoproteomic. These samples were selected from an initial cohort of 143 MIBC tissues and filtered by tumor purity, clinical history, pathological response, and proteomic quality control metrics. The final cohort comprised samples from 53 patients, including 45 with both genomic and proteomic data and 8 with genomic data only.Our multi-omics-based clustering reveals subtypes associated with chemotherapy sensitivity. Protein abundance of a short isoform of ATAD1 and RAF family proteins were identified as biomarkers of chemosensitivity which highlights the importance of proteomics data. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive benefit of combination therapy targeting these proteins. Our data analysis clearly demonstrates that proteogenomic plays an important role in uncovering potential resistance mechanisms that operate only at protein and Post-Translational Modification (PTM) levels. Proteomics data can be accessed through PRIDE with ID PXD060290. RNA-seq and whole-exome sequencing (WES) FASTQ files are archived in the dbGaP database.

  Study phs004049

• Blood and Marrow Clinical Trials Network Trial of Non-Myeloablative Conditioning and Transplantation of Umbilical Cord Blood For Hematologic Malignancies (BMT CTN-0604-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To examine the safety and effectiveness of a non-myeloablative stem cell transplant using umbilical cord blood as a treatment option for patients with leukemia or lymphoma and no suitable related donor.Background: Chemotherapy is a common treatment option for patients with aggressive forms of the blood cancers leukemia and lymphoma, but other treatment methods may need to be considered if the cancer does not respond well to chemotherapy, or if the cancer returns. In such cases, it may be recommended that the patient receive a stem cell transplant, commonly using donated bone marrow. A first degree relative is likely to be the best candidate for donation if the human leukocyte antigen (HLA) markers are a sufficient match. For patients lacking a HLA-matched related donor, it is routine to initiate an unrelated donor search. However some patients, particularly ethnic minorities, experience disease progression while awaiting identification of a suitably HLA-matched donor. Recently, stem cell transplants using umbilical cord blood have become a viable alternative option to treat these types of cancers.Typically patients undergoing a stem cell transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor stem cells. In this study, participants received a type of stem cell transplant called a non-myeloablative transplant, which is a reduced intensity conditioning (RIC) method of transplantation that does not require high doses of chemotherapy. RIC can be preferable in patients that are older and less clinically fit, and therefore less able to withstand the chemotherapeutic agents' toxicity levels.The BMT CTN 0604 study was one of two parallel multicenter phase 2 studies; the other of which was BMT CTN 0603, which used partially HLA-mismatched related bone marrow (Haplo-marrow) transplantation. The goal of these studies was to generate pilot multicenter data to support a future phase 3 randomized clinical trial.Participants: Patients less than 71 years of age with acute leukemia or lymphoma and lacking a suitable HLA-matched related donor were eligible to participate. Patients less than 22 years of age were eligible if they were ineligible for the BMT CTN 0501 trial. Acute leukemia was required to be in morphologic complete remission. Large-cell, mantle-cell, and Hodgkin lymphomas were required to have achieved at least a partial remission with treatment before allogeneic hematopoietic cell transplantation. Low-grade lymphoma patients were required to have failed two prior chemotherapy regimens. Patients who had undergone prior autologous transplantation were not excluded as long as three months had elapsed since the procedure. Participants were also required to have adequate organ function, including a left ventricular ejection fraction of at least 35% and specific liver, kidney, pulmonary, and physical functioning scores within acceptable ranges. A total of 54 individuals were enrolled in the study and 50 were included in the analysis.Design: Participants underwent a reduced intensity conditioning regimen prior to receiving the double umbilical cord blood (dUCB) transplant, which included two chemotherapeutic agents, cyclophosphamide and fludarabine, and a small dose of radiation. Cyclophosphamide was administered intravenously at 50 mg/kg six days before the transplant. Fludarabine was administered intravenously at 40 mg/m2 (adjusted for creatinine clearance) each day for five days before the transplant. A single dose of 200 cGy total body irradiation was performed one day prior to transplantation. Participants also received cyclosporine and mycophenolate mofetil (MMF) beginning three days before the transplant as prophylaxis for graft-versus-host-disease (GVHD). Participants could receive tacrolimus instead of cyclosporine.At transplantation, patients received two partially HLA-matched umbilical cord blood units from unrelated donors. The maximum allowable mismatch between the UCB unit and the recipient, or between the UCB units, was 2 of 6 HLA loci. Each unit contained a minimum of 1.5 × 107 nucleated cells, or 2.0 × 107 for units that were not red cell depleted, per kilogram of recipient weight. Units were thawed and infused per institutional practice after validation using methods approved by the study. After transplantation, filgrastim, a granulocyte-colony stimulating factor, was initiated at 5 μg/kg a day and continued until the absolute neutrophil count was at least 2000/μL for three consecutive days. Participants continued to receive MMF for 30 days after the transplant or 7 days after engraftment, whichever was later, and cyclosporine or tacrolimus until 180 to 200 days after the transplant. Supportive care, including blood product administration, prophylaxis, therapy for infection, and treatment of GVHD, was at the discretion of treating physicians and transplantation center practices.The primary outcome was participant survival from the time of transplant to 180 days. Secondary end points included progression-free survival and cumulative incidences of hematopoietic recovery, acute or chronic GVHD, relapse, and non-relapse mortality.Conclusions: Survival at 180 days after double umbilical cord blood transplant was 74%. Collectively, the results of BMT CTN 0603 and 0604 confirm the utility of dUCB and Haplo-marrow as alternative donor sources for reduced intensity conditioning hematopoietic cell transplantation, providing a rationale for an additional clinical trial to assess the relative efficacy of these two strategies.

  Study phs004890

• A Phase II Study: CRS207/GVAX Plus Anti-PD1 and Anti-CTLA4 Recruits Mesothelin- and KRAS-Specific T cells into PDAC

  This study examined immunologic correlatives from a phase II study evaluating CRS207/GVAX vaccines in combination with anti-PD1 and anti-CTLA4 in metastatic pancreatic cancer (NCT03190265). Arm A received CRS207/GVAX with anti-PD1 and anti-CTLA4 therapy; Arm B received CRS207 with anti-PD1 and anti-CTLA4 therapy. Patients undergoing treatment in this trial had peripheral blood mononuclear cells (PBMCs) and tumor tissue biopsied serially at pre-treatment and on-treatment timepoints. Single-cell RNA/TCR sequencing was employed on PBMCs. Bulk RNA/TCR sequencing was employed on tumor tissues. We identified treatment-enriched inflammatory pathways as well as T cell repertoires.

  Study phs003798

• Correlative Studies in Protocol GU16-287, which Studied Gemcitabine + (Carboplatin or Oxaliplatin) + Nivolumab in Metastatic Urothelial Cancer, which Included Collaboration with CIMAC-CIDC (Cohort 1 of 3)

  Purpose: Oxaliplatin has demonstrated the ability to sensitize tumors to immune checkpoint blockade through its immunomodulatory properties in model systems of cancer. This randomized trial aimed to evaluate gemcitabine/oxaliplatin and gemcitabine/carboplatin, each combined with nivolumab, in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Patients and Methods: Cisplatin-ineligible patients with mUC were randomized 1:1 to gemcitabine/carboplatin plus nivolumab or gemcitabine/oxaliplatin plus nivolumab for up to 6 cycles, followed by nivolumab monotherapy. A pick-the-winner design was employed with objective response rate (ORR) as the primary endpoint. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory analyses evaluated plasma protein analytes, circulating immune cell populations, and circulating tumor cells. Results: Forty-nine patients were enrolled (carboplatin arm, N = 25; oxaliplatin arm, N = 24). The ORR was 69.6% (95% confidence interval [CI] 0.48–0.87) for the carboplatin arm and 33.3% (95% CI 0.15–0.57) for the oxaliplatin arm. Median OS was 24.74 months and 16.43 months for the carboplatin group and oxaliplatin arms, respectively (hazard ratio 1.99, 95% CI 0.94–4.22; p = 0.07). Exploratory biomarker analyses revealed sustained adaptive immune activation in the carboplatin arm and features suggestive of tumor-promoting inflammation in the oxaliplatin arm. Conclusions:Oxaliplatin-based chemo-immunotherapy, versus carboplatin-based chemo-immunotherapy, did not yield a higher response rate, challenging assumptions based on preclinical data.

  Study phs004060

• Durvalumab and Cediranib with and without Olaparib in Recurrent Ovarian Cancer: A phase II Proof-of-Concept Study

  We report the efficacy and translational research findings of durvalumab, olaparib, and cediranib (D+O+C) and durvalumab and cediranib (D+C) therapies from the recurrent epithelial ovarian cancer (EOC) cohort within a single center, multi-arm, non-randomized, multi-cohort phase I/II trial (NCT02484404). Sixty-eight patients were enrolled (39 in D+O+C, 29 in D+C). The objective response rate (ORR) was 19.4% (95% CI, 9.5-43.5) for D+O+C and 29.6% (95% CI, 13.8-46.9) for D+C. Median progression-free survival (PFS) was 4.5 months in both arms, with each arm including four exceptional responders (PFS ≥ 12 months). Pre-treatment biopsies and paired normal peripheral blood mononuclear cells (PBMC) samples for whole exome sequencing (WES) were available for 31 patients in the D+O+C and 24 in the D+C, the remaining 13 patients were not biopsied due to safety concerns or being off treatment. WES was conducted to explore genomic profiles for potential correlations with clinical benefit (CB; partial response or stable disease [SD] with PFS ≥ 4 months) or no clinical benefit (NCB; progressive disease or SD with PFS TP53 mutations were found in most cases in both D+O+C and D+C arms. Overall, no consistent associations between baseline genomic alterations and CB were observed.

  Study phs004519

• NCTN: A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed with Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor either as Initial Therapy or after Tamoxifen (NCIC-MA.17R)

  Study ID: NCIC-MA.17RNCT Number: NCT00754845 Canadian Cancer Trials Group (CCTG)Submitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed with Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor either as Initial Therapy or after Tamoxifen (NCIC-MA.17R)Trial Description: RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy.PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy. Clinical data presented in the following publication(s):PMID 27264120 Disease type(s): Breast Neoplasm - Breast Cancer - InvasiveClinical Dataset(s) included:NCT00754845-D1 (PMID 27264120): There is one dataset for NCIC-MA.17R's primary publication 27264120. This dataset contains number of major protocol violations, time from diagnosis to randomization, baseline characteristics, hormone receptor status, sites of recurrence, survival, toxicity, stratification factors, cause of death, and QOL data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004248

• Somatic Evolution in Li-Fraumeni Syndrome

  In this study, we used ultradeep duplex sequencing (~15,000× depth) to measure somatic evolution in blood samples from a family of three individuals with Li-Fraumeni Syndrome (LFS) caused by an inherited TP53 pathogenic variant (p.R181H), and compared them to a cohort of unaffected controls using a set of genes related to Clonal Hematopoiesis of Indeterminate Potential (CHIP)/Acute Myeloid Leukemia (AML), as well as a mutagenesis panel designed to examine mutagenic processes. We found that individuals inheriting a single mutated copy of TP53 may experience less positive selection for subsequent TP53 mutations, as evidenced by a deficit of coding TP53 mutations, reduced dN/dS, and low predicted pathogenicity among the TP53 somatic mutations that do occur. However, the overall degree of mutagenesis in genomic regions without strong selection was higher in LFS patients. In addition, we investigated how LFS affects clonal evolution across multiple tissue contexts in one individual carrying p.R181H who succumbed to metastatic esophageal cancer.The data available through dbGaP includes BAM files, MAF files (mutation data), and genomic MUT files (showing per-position depth of sequencing), from ultradeep duplex sequencing of multiple tissues from a LFS patient as well blood samples from family members and controls.

  Study phs004484

• Prostate Cancer Upgrading Reference Set

  This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

  Study phs003670

• Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To evaluate whether a centralized, remote clinical pharmacy service could improve guideline adherence and secondary measures of cardiovascular risk in primary care offices in rural and small communitiesBackground: More than 2200 Americans die of cardiovascular disease every day. Team-based care and medication therapy management have become useful strategies to reduce gaps in the delivery of guideline-concordant therapy for cardiovascular therapy. Physician offices, especially in rural and smaller communities, lack the resources to implement team-based care with pharmacists who can provide medication therapy management. The ICARE trial developed a physician-pharmacist collaborative model to provide virtual clinical pharmacy services from a central location to 12 family medicine offices in Iowa to evaluate whether a centralized, remote clinical pharmacy service could improve outcomes.Participants: Subject inclusion involved 3 separate processes. First, subjects were required to be an English-speaking male or female over the age of 50 who had been seen in the clinic/practice at least once in the past 24 months. Second, subjects were required to have at least one of the following conditions: uncontrolled diabetes (hemoglobin A1c > 7.5%); low-density lipoprotein cholesterol (LDL-C) > 110 mg/dl for patients with a history of peripheral artery disease, coronary artery disease, stroke, transient ischemic attack, or diabetes, elevated blood pressure with systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg in persons with diabetes or chronic kidney disease, or systolic BP ≥ 150 mmHg or diastolic BP ≥ 90 mm Hg in persons with uncomplicated hypertension. Third, subjects were required to additionally have three or more of the following cardiovascular conditions or risk factors: history of myocardial infarction, coronary artery disease, stroke, transient ischemic attack, atrial fibrillation, peripheral vascular disease/claudication, current smoker, or obesity with BMI > 30.Exclusion criteria included diagnosis of primary pulmonary hypertension, a cancer diagnosis with a life expectancy of less than 2 years, residence in a nursing home or diagnosis of dementia, no telephone access or a hearing impairment that prevented telephone use, or patient had plans to move from the area or transfer care to a different clinic in the next 12 months.In total, there were 302 subjects enrolled in the ICARE trial. Of these, 259 subjects completed the 12-month visit.Design: The study included 11 private physician offices and one Federally Qualified Health Center. Offices were identified from the Iowa Research Network and screened for their ability to conduct the trial, enroll subjects, and meet quality control measures. A Study Coordinator employed in each office identified, screened, and recruited subjects. All subjects and physicians in a given office received either the intervention or usual care.Blood pressure, hemoglobin A1c, and LDL cholesterol were collected at baseline and 12 months regardless of whether the subject had a diagnosis of hypertension, diabetes, or hyperlipidemia. Baseline data were collected on case report forms by Study Coordinators and entered centrally by the research team.Three clinical pharmacy specialists located within the research offices of the principal investigator provided the intervention. Pharmacists were required to have a Doctor of Pharmacy degree and a minimum of one year of clinical residency (or equivalent practice experience). The pharmacists travelled to each intervention office to be introduced to the providers and facilitate team-building before the intervention started. These sessions explored the providers' preferred methods and frequency of communication with the pharmacists based on other telemedicine studies. Pharmacists had access to the baseline data, including BP and laboratory values, which they used to reconcile medications and update the medical records. Pharmacists monitored blood glucose values, BP readings, laboratory values, and potential adverse events from the EMR or from the patient in order to recommend medication changes to the treating medical provider. Interventions for physicians were directed at improving guideline adherence for reducing CV risk and preventive care based on the Guideline Advantage (GA) criteria.Each subject was assigned to one of the three pharmacists to maintain continuity. Subjects were assigned to the pharmacists in the order they were enrolled into the study, independent of medical office. Subjects were primarily contacted by telephone and counseled by the pharmacists about beneficial health behavior changes related to tobacco use, diet, physical activity, and alcohol consumption. Medications and dosages were reconciled. The pharmacists identified problems related to poor disease control, subject misunderstandings, poor medication adherence or failure to receive preventive health services, adverse effects, drug interactions, and cost. Pharmacists provided patient education when problems were identified and developed a plan for follow-up contacts, generally every 1-2 weeks by telephone if there were continuing problems or medication issues. The primary outcome measure was adherence to the GA criteria.Conclusions: There was no improvement in the GA score from baseline to 12 months in the control group. There was a statistically significant improvement in the intervention group in the GA score plus several criteria were significantly better for intervention subjects including appropriate statin therapy, body mass index (BMI) screening and alcohol screening. Only 13.7% of subjects with diabetes had hemoglobin A1c at goal at baseline and this increased to 30.8% and 21.0% in the intervention and control groups, respectively, at 12 months.The improvements in outcomes were modest and not statistically significant, due to higher-than-anticipated baseline guideline adherence and greater inter-office variability than anticipated.

  Study phs004679

• Epigenomics of Neurocognitive Function in Breast Cancer

  This study harnessed the data and biospecimens from the Exercise Program in Cancer and Cognition (EPICC) study (parent study) that collected data on cognitive function, demographics, other symptoms and biospecimens at two time points (T1: enrollment, T2: six months later) within the context of a six-month randomized controlled trial of a moderate intensity aerobic exercise intervention. This study collected genome wide DNA methylation data from T1 and T2 and conducted epigenome-wide association-based analyses to find genes and biological pathways explaining variability in cognitive function and explaining how exercise mitigates cognitive decline. Our initial findings identified cg10331779 near CTNND2 (p-value=9.65×10-9) associated with processing speed and cg25906741 in MLIP (p-value=2.01×10-8) associated with subjectively measured cognitive function. Additionally, differentially methylated regions were identified near SLC6A11, PRKG1/CSTF2T, and FAM3B for processing speed and near PI4KB and SGCE/PEG10 for mental flexibility.

  Study phs003959

• Human GPR15 Deficiency Reveals CD8+ T Regulatory Cell-Macrophage Crosstalk in Intestinal Inflammation

  Inflammatory bowel disease (IBD) causes lifelong suffering from gastrointestinal inflammation and dysfunction with severe complications including colon cancer. The disease is increasing in global prevalence, and current therapies are insufficient, highlighting an urgent need to understand its pathogenic mechanism. We reported multiple patients with GPR15 deficiency which result in severe early-onset IBD. GPR15, a G protein-coupled receptor (GPCR), expressed in immune cells and previously described as an entry co-factor for human and simian immunodeficiency viruses, is a crucial marker and homing receptor for a unique subset of intramucosal GPR15-guided regulatory CD8+ T lymphocytes (CD8+ TIGR). These cells potently kill macrophages that become aggressively activated in response to intestinal damage or disease. Thus, our identification of CD8+ TIGR cells yields new insights into organ-specific immune regulation and potential treatment strategies for IBD.

  Study phs003950

• Combined PDCD1, BRAF and MAP2K7 Inhibition in BRAFV600E Colorectal Cancer: A Phase 2 Trial

  In this study, we evaluated the clinical efficacy of combined PDCD1, BRAF, and MAP2K7 inhibition in metastatic BRAFV600E Colorectal Cancer (CRC) patients (NCT03668431). We performed bulk whole exome sequencing (WXS) and bulk RNA sequencing (RNA-Seq) in 35 pre-treatment tumor biopsies and matching germline for tumor mutational burden (TMB), BM1/BM2 transcriptional subtypes, and consensus molecular subtypes (CMS) analysis, which were previously reported to affect prognosis and response to therapy (PMIDs: 32047001, 27354468, and 26457756). Analysis of bulk data showed that TMB, BM1/BM2 subtypes, and CMS did not correlate with clinical response in this study. Analysis of single cell RNA sequencing (scRNA-Seq) data of tumor epithelial cells from 23 paired day 0 and day 15 tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome.

  Study phs003178

• Childhood Cancer Data Initiative (CCDI): Single-Cell Atlas of NF1 Nerve Sheath Tumors

  The worst outcome of NF1 is the development of the aggressive and highly metastatic malignant peripheral nerve sheath tumors (MPNST), which transform from benign plexiform neurofibroma (PN) and lack effective treatment. In this study, we performed single-cell RNA sequencing of 63 clinically annotated NF1-associated peripheral nerve sheath tumors, including 24 PN, 34 premalignant atypical neurofibromas, and 5 MPNSTs. These results improve the ability of identifying high-risk neurofibromas and provide a unique opportunity for early detection of MPNST.

  Study phs003519

• Single Cell RNA-Sequencing of BCG Naive and Recurrent Non-Muscle Invasive Bladder Cancer Reveals a CD6/ALCAM-Mediated Immune-Suppressive Pathway

  Non-muscle invasive bladder cancer (NMIBC) represents 70–80% patients with newly diagnosed bladder cancer, and Bacillus Calmette-Guerin (BCG) remains a cornerstone treatment for intermediate- and high-risk NMIBC to prevent disease recurrence and progression. However, a significant number of patients experience recurrence after their first course of BCG, posing significant challenges in the management of the disease. We conducted single cell RNA sequencing (scRNA-Seq) on freshly collected NMIBC samples, distinguishing between those naive to BCG treatment and those that recurred post-BCG treatment. We observed a clear activation of inflammatory pathways across cell types during recurrence, but these were not associated with canonical immune checkpoint or T cell exhaustion phenotypes. Analysis of cell-to-cell communication revealed enhanced interactions between T cells and urothelial cells in BCG-recurrence, predominantly modulated by CD6 and activated leukocyte cell adhesion molecule (ALCAM). Furthermore, we found CD6hi T cells to be immunosuppressed and enriched in recurrent samples, suggesting a potential role for CD6 as an immune evasion signal in NMIBC.

  Study phs003742