5709 results for "canc*"

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• Therapeutic Targeting of ATR Yields Durable Regressions in High Replication Stress Tumors

  Patients with relapsed or recurrent small cell lung cancer or extra-pulmonary small cell cancers were enrolled on an investigator-initiated, single-arm, phase 2 trial (NCT02487095) combining an ATR inhibitor M6620 (VX-970, berzosertib) administered at 210 mg/m2 intravenously over 60 minutes on day 2 and day 5, and topotecan 1.25 mg/m2 intravenously over 30 minutes every 23 hours on days 1 through 5, with a support of pegfilgrastim 6mg subcutaneously on day 6 in 21-day cycles. Tumor samples were collected either just before starting the treatment or before starting treatment prior to be enrolled in the trial. Whole exome and RNA were sequenced to evaluate genomic and transcriptomic characteristics associated with the response to the combination treatment.

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• Kids First and INCLUDE: Down Syndrome, Heart Defects, and Acute Lymphoblastic Leukemia

  This project is a collaboration with the trans-NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, which seeks to improve health and quality-of-life for individuals with Down syndrome, and NHLBI's TransOmics for Precision Medicine (TOPMed) program, which seeks to apply omics technologies to improve scientific understanding of the fundamental biological processes that underlie heart, lung, blood, and sleep (HLBS) disorders. The data is also available at the INCLUDE Data Hub. Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital heart disease (CHD) and acute leukemia. For instance, children with DS have a 2000-fold increased risk of atrioventricular septal defects (AVSD) and a 20-fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both of these phenotypes, however, the genomic architecture of risk remains largely undiscovered. In this joint Kids First/TOPMed/INCLUDE project, we are currently including >2,000 samples for whole-genome sequencing, including: 1) paired germline-tumor samples from children with DS-ALL; and 2) samples from families with DS-CHD. This work will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer. The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Therefore, the aims of our study are: 1) compare whole-genome sequencing (WGS) data between children with documented DS-AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development; and 2) compare WGS data between children with documented DS-ALL and children (from Aim 1) with DS who do not have a known history of ALL. We will also examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-AVSD and DS-ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer. Additional Pediatric Cardiac Genetics Consortium (PCGC) data from children affected with Down syndrome and congenital heart disease are accessible through two separate dbGaP studies: phs001138 (Kids First) and phs001194 (TOPMed).

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• Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

  Oncogenic alterations in EGFR frequently co-occur with additional genetic alterations in EGFR-driven lung adenocarcinoma (LUAD), but how specific combinations of mutations affect tumor phenotypes and responses to targeted therapy is yet unknown. We leveraged a genetically engineered mouse model of EGFR mutant/Trp53-deficient LUAD to study the consequences of inactivating 10 different tumor suppressor genes on the fitness and tyorosine kinase inhibitor (TKI) sensitivity of these tumors. We found that loss of Keap1 is associated with a reduced response to therapy. In patients, we found that mutations in the KEAP1/NFE2L2/CUL3 pathway are associated with a significantly shorter time to treatment failure for EGFR TKI therapy compared to matched patients with wild-type KEAP1/NFE2L2/CUL3 tumors. We also analyzed whole exome sequencing data from tumor specimens before TKI treatment and at the time of treatment resistance for mutations in the KEAP1 pathway and these data are being submitted here.  

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• Dana-Farber Cancer Institute (DFCI) Wu Lab/Avicenne CLL RNA-Seq Study

  Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+ B cells in peripheral lymphoid organs, bone marrow and blood. Recently, the advent of large-scale whole-exome sequencing of hundreds of CLL samples has led to gain a comprehensive understanding of the mutational landscape of this clonal B cell malignancy, but the functional effects of the putative driver mutations thus discovered are largely unknown. In this study, we analyze RNA-seq data from CLL patients to characterize dysregulated biological pathways regarding the presence of recurrent mutations. Source of tumor is patients' PBMC isolated from peripheral blood using the Ficoll method. Purity was confirmed using flow cytometry flow (>80% in all cases).

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• Study of Tumor Recurrence Related to the Expression of the PAX3-FOXO1 Oncogenic Transcription Factor in Fusion-Positive Rhabdomyosarcoma

  Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft tissue cancer characterized by a recurrent 2;13 chromosome translocation. This translocation generates a PAX3-FOXO1 (P3F) fusion gene, which encodes a chimeric transcription factor with oncogenic activity. Using a human myoblast system that models targeted therapy directed against P3F, we demonstrated that the expression of the fibroblast growth factor 8 (FGF8), a direct transcriptional target of P3F, is necessary and sufficient for PAX3-FOXO1-independent tumor recurrence in addition to be required for the tumorigenic activity of primary tumors expressing P3F. In addition, we showed that FGF8 is expressed in human rhabdomyosarcoma cell lines that express P3F. We also demonstrated that FGF8 contributes to their proliferation and transformation in vitro, and is sufficient to maintain their oncogenicity after the loss of P3F expression. We suggest that targeting the expression of the PAX3-FOXO1 transcription factor can generate resistance and recommend that additional anticipated therapeutic approaches, such as targeting FGF8 pathway, may avoid this resistance mechanism.

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• Characterization of Immune-Related Gene Expression in Lung Cancer

  We performed a comprehensive analysis of inter- and intratumor heterogeneity of immune gene expression in 160 lung cancer patients from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. The transcriptome was profiled with RNA sequencing in 269 tumor samples and 110 normal tissue samples from 160 subjects.

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• PDAC Prognosis Biomarkers in Genomic and Transcriptomic Molecular Data

  Our study was designed to identify biomarkers related to the prognosis of Pancreatic Ductal AdenoCarcinoma (PDAC) patients using genomic variants and gene expression in coding regions of the human genome (exome). PDAC is the 7th cause of cancer deaths and is among types of cancer having the poorest prognosis. To improve treatment outcomes of PDAC, biomarkers related to PDAC prognosis are needed. The goals of our study are to find genomic and transcriptomic biomarkers, which can classify prognosis subtype of PDAC patients, and eventually to predict subtypes or prognosis for each patient. In this study, we generated Whole Exome Sequencing (WES) and exome capture RNA sequencing data of 450 tumor and matched normal samples from 150 PDAC patients. Our data may be useful for understanding genomic and transcriptomic features, prognosis prediction, and precision medicine for PDAC.

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• Lineage Plasticity and Immune Cell Heterogeneity Are Coordinately Dysregulated Through Changes in FOXA1 Expression in Bladder Cancers with Squamous Differentiation

  We performed whole exome sequencing (WES) of paired, macrodissected regions of urothelial carcinoma (UC), not otherwise specified (NOS-UC) and squamous differentiation (SqD) from 21 bladder tumors in which distinct and separable NOS-UC and SqD regions were present (total 42 exomes, in addition to matched normal exomes). Mean tumor mutational burden (TMB) was higher in the SqD versus the NOS-UC regions. Consistent with the higher TMB, the SqD regions also had a higher neoantigen burden than the patient-matched NOS-UC regions. The SqD regions also exhibited higher karyotypic complexity with a higher median ploidy relative to the paired NOS-UC regions. Phylogenetic analysis of the WES data confirmed that the morphologically distinct regions of all 21 tumors arose from a shared precursor with a median of 68 (range 16 – 852) non-synonymous mutations shared between the NOS-UC and SqD regions, and the overall data were indicative of early branched evolution. As whole exome sequencing did not identify a shared mutational alteration or genomic signature unique to the SqD or NOS-UC components, we therefore performed expression profiling of separable SqD and NOS-UC regions of 12 bladder tumors from the WES cohort with RNA quality sufficient for whole transcriptome RNA-sequencing (RNAseq, total of 24 regions). Based on centroid clustering analysis of expression data, all 12 regions of SqD were basal-squamous subtype based on the TCGA molecular classification schema. Notably, 8 of the NOS-UC regions were also basal-squamous subtype, with only four pairs exhibiting discordant transcriptional subtypes (three NOS-UC regions were luminal-infiltrated, one luminal-papillary). To better quantify differences in the transcriptional profiles of the paired NOS-UC and SqD regions, we used single sample gene set enrichment analysis (ssGSEA) to assess for enrichment of luminal or basal-squamous gene expression. ssGSEA analysis revealed that the SqD regions expressed higher levels of basal-squamous genes based on the BASE47 gene set and UPK/KRT gene sets; whereas the matched NOS-UC regions expressed higher levels of luminal genes. These differences in the levels of expression of basal and luminal genes were observed even in cases in which both the NOS-UC and SqD regions were basal-squamous subtype based the TCGA molecular classification schema. Exomes from eight patients in this study have previously been deposited in dbGaP: accession number phs001783 as part of the study "Exome Recapture and Sequencing of Prospectively Characterized Clinical Specimens From Cancer Patients".

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• Human Tumor Atlas Network (HTAN)

  An NCI-funded Cancer Moonshot initiative to construct 3-dimensional atlases of the dynamic cellular, morphological, and molecular features of human cancers as they evolve from precancerous lesions to advanced disease.

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• Characterizing TP53 and PPM1D Mutations as Resistance Drivers to Radiation Therapy in Diffuse Intrinsic Pontine Gliomas

  Pediatric high-grade gliomas (pHGGs), encompassing diffuse midline gliomas (DMGs) and hemispheric tumors, represent the most common cause of cancer-related deaths in children age 0-14 years. Over the last decade, several landmark papers have revealed recurrent single nucleotide variants (SNVs) in the core histones H3.3 and H3.1, co-occurring with alterations in the TP53 signaling pathway and receptor tyrosine kinases (RTKs). However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored. We performed a comprehensive analysis of whole genome sequencing (WGS) data on pediatric high-grade gliomas (pHGGs) from 179 children, including 61 hemispheric tumors and 118 diffuse midline gliomas, or DMGs, of which 61 are novel to this study. Among the DMGs, 84 (71%) were from pre-treatment biopsies including 33 obtained from the first multi-institutional North American clinical trial to incorporate diagnostic biopsies. This represents the largest cohort of pretreatment DMGs with whole genome sequencing to date. This large cohort of whole genome sequences provides an unparalleled opportunity to assess significantly recurrent structural variants in pHGG and their associations with driver SNVs and SCNAs. 

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• Ghana Breast Health Study

  The Ghana Breast Health Study (GBHS) was a multi-disciplinary, population-based case-control study conducted in Accra and Kumasi, Ghana that was designed to investigate breast cancer etiology in the West Africa region. The study enrolled 1,126 invasive breast cancer cases and 2,106 frequency matched population-based controls using census-based sampling. GHBS participants were between the ages of 18 to 74 years of age. Breast cancer cases were recruited at the time they presented with lesions suspicious of breast cancer at three hospitals: Korle Bu Teaching Hospital (Accra), Komfo Anoyke Teaching Hospital (Kumasi) and Peace and Love Hospital (Kumasi). These hospitals are the primary providers of treatment for breast cancer in Ghana, allowing for cases in our study to represent most breast cancers diagnosed in these areas during the study period. The following publications describe the GBHS in detail: 1) Brinton LA et al. Design considerations for identifying breast cancer risk factors in a population-based study in Africa. Int J Cancer 2017;140:2667-2677 (PMID:28295287). 2) Nyante SJ et al. Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study. PloS one 2019;14:e0215347 (PMID:30990841)Among subjects with an available source of germline DNA genotyping was performed using the Infinium Global Screening Array-24 per the manufacturer’s guidelines using the Infinium automated protocol. We excluded probable duplicates and close relatives, and samples with a call rate < 95% or samples with extreme heterozygosity. Female sex was verified by Identifiler using X chromosome heterozygosity and the X chromosome inbreeding coefficient F statistics. The GLU genetics’ ld.tagzilla module was used to confirm African ancestry. To resolve more detailed population substructure, principal components analysis was conducted among all unrelated subjects using the EIGENSOFT v7.2.1. Imputation was performed using the Michigan imputation server Minimac3 with 1K genomes phase3 as reference panel.

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• Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

  In this study, we performed metabolite profiling and RNA-sequencing on human breast cancer tumors and normal breast tissue samples, including triple negative breast cancer (TNBC), estrogen receptor positive breast cancer (ER+) and paired normal samples, and patient-derived xenografts (PDX) samples. Here, we report two distinctive groups defined by metabolites; a TNBC-HIGH group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and an ER-HIGH group that shows high levels of fatty acid and arginine biosynthesis intermediates. We identify different metabolic enrichment profiles between cell lines grown in vitro vs. in vivo; cell lines grown in vivo recapitulate patient tumors metabolic profiles. Further, we identify a subset of genes that strongly correlates with the TNBC-HIGH metabolic profile using integrated metabolic and gene expression profiling, which strongly predicts patient prognosis when tested on larger human datasets. As a proof-of-principle, when we target TNBC-HIGH metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines, murine p53-null mammary tumors, and in vivo patient-derived xenografts (PDXs) upon multi-agent drug treatment. This study highlights potential new therapeutic opportunities in breast cancers guided by a genomic biomarker, which could prove impactful for breast cancers that rapidly proliferate.

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• Genomics of Prostate Cancer

  This dataset includes genomic data from patients with prostate cancer. Specimens include archival active surveillance biopsies, radical prostatectomy specimens selected based on evidence of PD-L1 expression and/or T lymphocyte infiltrates, and rapid autopsy material from patients deceased of prostate cancer. These data include low pass whole genome sequencing and targeted sequencing with matched normal.

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• A Single Cell Atlas of MMRd and MMRp Colorectal Cancer

  Immune responses to cancer vary across cancer types and patients. Colorectal cancer tumors with mismatch repair-deficiency (MMRd) show an elevated immune cell activity as compared to mismatch repair proficient (MMRp) tumors. To understand the immune response patterns in these two types of colorectal cancer, we transcriptionally profiled 371,223 tumor and adjacent normal cells from 28 MMRp and 34 MMRd patients. Unsupervised analysis identified 88 cell subsets, from 7 distinct cell clusters (that contain epithelial, malignant, stromal and immune cell lineages), and an associated compendium of 204 gene expression programs. Examination of these cell subsets and programs revealed extensive transcriptional and spatial remodeling of malignant, stromal and immune cells in MMRd and MMRp tumors. This dataset was generated as part of a published study (Pelka, Hofree, Chen, et al., Cell 2021 Sep 2;184(18):4734-4752; PMID: 34450029).

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• Genome Instability in Mammary Cells of Pathogenic BRCA1/2 Mutation Carriers

  It remains unknown if inherited germline mutations in the BRCA1 or BRCA2 gene increase the risk of breast and ovarian cancer by elevating mutation rate in mammary cells. Here we show, using a single-cell whole genome sequencing approach, that mammary luminal epithelial cells isolated from tissues obtained from preventive mastectomy surgeries in women with a pathogenic BRCA1/2 germline mutation, exhibit a statistically significant, increased mutation frequency as compared to age-matched controls without genetic risk of breast cancer.

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• Integrative Molecular Characterization of Breast Cancer

  We have performed integrative analyses of breast cancer tumors, including whole exome sequencing of tumor & normal pairs, whole transcriptome sequencing, and single-cell/nucleus RNA sequencing, to determine molecular correlates of response to novel and immune therapies. We have focused on dissecting the role of anticancer immunity in response to these therapies and understanding biological mechanisms underlying therapeutic resistance. The goal of this work is to advance a precision medicine approach to breast cancer treatment by identifying molecular biomarkers to improve therapy selection and novel therapeutic targets to overcome resistance. 

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• Tandem DNA Repeats Activate hTERT Gene Transcription

  Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell and chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of E-boxes, cooperated with the proximal promoter in hTERT regulation by bHLH transcription factors and maintained hTERT expression during embryonic stem cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations.  To assess the genetic polymorphism of VNTR2-1 in human populations, we analyzed genomic DNA samples of Caucasian Americans and African Americans enrolled in the Georgia Centenarian Study.  VNTR2-1 in these genomic DNA samples were PCR amplified and subjected to sequencing analysis usinb the PacBio® SMRT method. The result showed that all VNTR2-1 alleles in Caucasian Americans contained 76 or more 42-bp repeats, whereas 32% of VNTR2-1 alleles in African Americans had fewer than 76 repeats.  

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• Childhood Cancer Data Initiative (CCDI): Genomic Analysis in Pediatric Malignancies

  Pediatric solid tumors are highly heterogeneous, encompassing a large number of histotypes. The genomic landscape of these diseases is characterized by few single-nucleotide variants (SNVs) compared to adult cancers. In contrast, many exhibit a high prevalence of structural or epigenetic changes that alter gene expression, underlining the need for comprehensive genomic approaches such as whole-genome sequencing (WGS). Several studies have specifically addressed the clinical utility of genomic analysis in the pediatric and AYA cancer setting. Review of these studies point to key challenges that must be addressed in order to advance the routine use of genomics in this population. We have established a large collection of solid tumor tissue samples through our biobanking efforts. Where possible, we obtain longitudinal samples from the same patient. These primary patient samples and their corresponding germline have been analyzed using whole genome and whole transcriptome sequencing methods and have been linked to clinical metadata using both manual curation and robust methods for automatic extraction from the electronic health record (EHR). Importantly, research-grade genomic analysis is performed in parallel to our CLIA-grade sequencing (“UCSF500”) efforts for some of the patients in this study cohort and have been submitted as part of the American Association for Cancer Research's project GENIE and/or the National Childhood Cancer Registry. For our sequenced tumor samples, we have retrospective clinical data and ongoing efforts to prospectively record key events throughout the patient's cancer journey. In our solid tumor program, we have developed many patient-derived xenograft models and a number of PDX-derived cell lines. These unique models have been evaluated using genomic and functional approaches including (in some cases) treatment with conventional chemotherapy or investigational agents. Lastly, these samples were collected from a population that is among the most diverse in the nation and includes significant numbers of Asian, Latino, Indigenous and African-American patients, groups that are traditionally underrepresented in many banking efforts.

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• Transcriptome and Epigenome of TIL Infusion for Cancer Immunotherapy

  Adoptive T cell therapy (ACT) using ex vivo–expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Samples were analyzed from TIL infusion products from metastatic melanoma human patients who responded to TIL-ACT (responders) and patients who did not (non-responders). Single cell transcriptome of TIL infusion products were analyzed for CD8 TIL phenotype and function. In patients with available neoantigen reactive TIL, single cell TCR clonotyping was performed to study anti-tumor TIL states between responders and non-responders. Epigenetic studies on TIL infusion products were performed using ATAC sequencing between paired CD39- C69- and CD39+ CD69+ CD8+ TILs.

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• Metformin for Oral Cancer Prevention

  The M4OC-PREVENT clinical trial addressed whether metformin has utility in the prevention of oral cancer. It is a phase IIa clinical trial of metformin ER 2,000 mg per day given for 12-14 weeks to individuals with oral premalignant lesions, either oral leukoplakia or erythroplakia (which are precursors to oral cancer). The goal was to determine if metformin decreases the size of oral leukoplakia (clinical response). Additionally, effects on biomarkers of cancer risk and metformin effect were ascertained. The clinical trial was performed at the University of California San Diego Moores Cancer Center, the University of Minnesota, and the British Columbia Cancer Agency, with monitoring and oversight provided by the University of Arizona.

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• Molecular Signatures of DCIS to Invasive Progression for Basal-Like Breast Cancers: An Integrated Mouse Model and Human Tumor Study

  We studied the genomic signatures of progression in breast ductal carcinoma in situ (DCIS) as it progresses towards triple negative invasive breast cancer (TNBC). Single cell RNA sequencing (scRNAseq) was performed on the C3Tag genetically engineered mouse model that forms human breast-like DCIS and TNBC. Bulk RNA sequencing was performed on RNA harvested from archival formalin-fixed, paraffin embedded (FFPE) pairs comprising of estrogen receptor (ER) positive (ER+) and negative (ER-) subsets of DCIS. 

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• Germline Genetic Variants in Cancer-Susceptibility Genes in Patients with Osteosarcoma

  We conducted whole-exome sequencing of germline DNA from patients with osteosarcoma to estimate the frequency of pathogenic/likely pathogenic germline genetic variants in known cancer-susceptibility genes in a large population of osteosarcoma patients unselected for family history.

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• HCI-PDX Trial Center for Breast Cancer Therapy

  The HCI-PDX Trial Center for Breast Cancer Therapy study is a collection of patient-tumor samples that are serially established as patient-derived tumor xenografts (human tumor in mouse) and matching organoids. For this study, we describe valuable methods and resources to generate organoids and use them as cost-effective models for precision drug screens. This study leveraged whole-exome sequencing, RNAseq, and SNP-array data to illustrate how the heterogeneity of tumors is preserved in xenograft and organoid models. Sequencing files are provided for whole-exome and RNAseq data. Processed copy number variant calls from the SNP arrays are also available. A full description of the study can be found in the article entitled, "A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology," written by Guillen et al., 2022 in Nature Cancer (PMID: 35221336).

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• Inhibition of CDK4/6 Promotes CD8 T Cell Memory

  Inhibitors of Cyclin-Dependent Kinase 4 and 6 (CDK4/6) have been recently deployed for the treatment of advanced breast cancer. Despite their success, the mechanism of action of these drugs is unclear. In mice, treatment with a CDK4/6 inhibitor improve T cell memory responses and protect mice against tumor rechallenge. We aimed to identify the correlates of this finding in human subjects. In this study, blood was collected from 5 breast cancer patients before and during treatment with the CDK4/6 inhibitors abemaciclib or palbociclib. Blood was also collected from 2 breast cancer patients who did not receive a CDK4/6 inhibitor. Recently activated CD8 T cells (CD45RO+ CD45RA+) were sorted and subjected to single-cell RNA sequencing.

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• Comprehensive Analysis of the Immunogenomics of Triple Negative Breast Cancer Brain Metastases from LCCC1419

  Triple negative breast cancer (TNBC) is an aggressive subset of breast cancer that lacks expression of the estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immunogenomics of BrM remains largely unknown. Thus, we conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to foster the development of immunotherapy strategies in this aggressive and clinically unmet disease.  

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