Search Results - EGA European Genome-phenome Archive

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-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. ObjectivesHypertension Study: To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.Lipid Study: To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least an additional CHD risk factor. BackgroundHypertension Study: Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.Lipid Study: Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups.ParticipantsHypertension Study: A total of 33,357 participants. Lipid Study: A total of 10,355 participants. Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years; 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes. DesignHypertension Study: A randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002. Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15,255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years. The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure (HF), and peripheral arterial disease).Lipid Study: Multicenter (513 primarily community-based North American clinical centers), randomized, non-blinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The interventions in the trial were pravastatin, 40 mg/d, vs usual care. The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included non-fatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer.ConclusionsHypertension Study: Thiazide-type diuretics are superior in preventing one or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.Lipid Study: Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.

Study phs004021

Pre-Existing Skin-Resident CD8 and γδ T Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immunotherapy. Here, we attempted to identify novel predictive biomarkers of response through extensive and deep multi-omics interrogation of 186 samples from 116 patients. We collectively integrated bulk RNAseq, single-cell RNAseq, multiplex immunofluorescence, and spatial transcriptomics. Importantly, we were also able to study 14 matched pairs of tissue samples from pre- and post-immunotherapy. In non-responders, tumors show evidence of increased tumor cell cycling, expression of neuronal stem cell markers, and IL-1α/β. Responders have evidence of increased type I/II interferon signatures and evidence of pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of multiple T cell receptors. Spatial transcriptomics demonstrated higher co-localization of T cells with B and dendritic cells in responders, with evidence of expression of chemokines important for co-stimulation. Finally, immunotherapy increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors in responders, further underscoring their therapeutic importance. These data identify potential novel actionable biomarkers and therapeutic targets for MCC.

Study phs003629

Analyzing Somatic Mutagenesis in Systemic Sclerosis

The study was undertaken with the aim of estimating differences in the mutational burden in lung tissues from healthy vs systemic sclerosis (SSc) patients. SSc is an auto-immune disease, with patients often developing cancer. However, the etiology of this phenomenon is poorly understood. As such we sought to uncover potential molecular mechanisms prevalent within SSc tissues that might be potentiating cancer. Samples were randomly collected from individuals from two broad ethnic groups, European (EA) and African American (AA). In total, samples were obtained from 7 individuals belonging to the EA group and 4 individuals from the AA group. For this study, ethnicity was not included as a confounding variable, given that the data set has roughly comparable number of individuals from both ethnicities for the healthy and SSc cohorts. Study participants ranged in age from 37-63 years old. Median age (52 years old) of healthy individuals was comparable to the SSc cohort (~48 years old). Participants were self-described as current/former smokers or non-smokers. Lung tissues were obtained under a protocol approved by the University of Pittsburgh Institutional Review Board. Written informed consent statements were provided to the University of Pittsburgh IRB by the study participants/patients. Sample sizes were determined by the ability of bulk lung fibroblast tissues to stably propagate in culture until single cell clones could be obtained. Samples for which sufficient cell density could not be achieved for downstream high-depth sequencing analysis were excluded from the study and are not reported. Five or greater than 5 samples are collected from each cohort including healthy and SSc patients. Subjects were allocated to two basic cohorts based on diagnosis at the time of explant. Participants with no reported lung anomalies were allocated to the "healthy" cohort, whereas individuals with reported lung abnormalities, primarily SSc with pulmonary fibrosis and/or hypertension were allocated to the "SSc" cohort. All tissue samples were cultured, propagated and processed in identical fashion without requiring individual-specific protocols. Additionally, equivalent amounts of DNA were used for preparing sequencing libraries from both cohorts, and all samples were sequenced using Illumina whole genome sequencing (WGS) and analyzed using identical computational pipelines. Our study primarily discovered that there is a significantly higher burden of somatic mutations in SSc samples, compared to healthy samples. We observed an overall increase in a range of mutations in genomes of SSc patients, including single base substitutions, indels, structural variants and copy number alterations. Additionally, we uncovered a novel mutation signature associated with SSc samples, hinting at the activity of POLH in these samples, and highlighting the potential nexus between inflammation, DNA damage, and cancer.

Study phs003700

CSER: Exome Sequencing in Diverse Populations in Colorado and Oregon/CHARM Cancer Health Assessments Reaching Many

The CHARM (Cancer Health Assessment Reaching Many) study, part of the Clinical Sequencing Evidence-Generating Research (CS.ER2) effort, aimed to assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population included adults at risk for hereditary cancer syndromes. The primary objective was the implementation of a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators aimed to assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators were also assessing the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.Sequencing and analysis for CHARM was conducted at the Northwest Clinical Genomics Laboratory, University of Washington, Seattle (https://nwgc.gs.washington.edu/).

Study phs002111

HINTS Geo-Coded Data 2014 (HINTS 4 Cycle 4)

The Health Information National Trends Survey (HINTS) is a nationally representative survey which has been administered every few years by the National Cancer Institute since 2003. HINTS 4 includes four mail-mode data collection cycles over the course of three years. Cycle 4 was conducted from August 19 through November 17, 2014. Cycle 4 was conducted by mail using a protocol similar to that used in Cycles 1, 2, and 3 with a goal of obtaining 3,500 completed questionnaires, with a final respondent sample of 3,677.

Study phs004209

Global Health Centers of Excellence-New Delhi (GHCoE New Delhi-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. ObjectivesProtocol 1 To develop a model surveillance system for cardio-metabolic diseases (CMD) and their risk factors which can be adopted for continuing surveillance by other countries in South East Asia. To measure the incidence of CMD risk factors and disease events, as well as the associated morbidity and mortality. Protocol 2 To test whether an intensive and comprehensive health care intervention to reduce cardiovascular disease (CVD) risk among type 2 diabetes patients in South Asia is more effective and sustainable compared to existing care.Protocol 3 To develop a model surveillance system for cardio-metabolic diseases (CMD) and their risk factors in rural India. To measure the incidence of CMD risk factors and disease events, as well as the associated morbidity and mortality.Background Although animal and ecologic studies have suggested a link between dietary fat and the incidence of breast cancer, previous observational studies have not yielded definitive results. In the Women's Health Initiative dietary trial, breast cancer incidence was not significantly different between the low-fat diet group and the control group. However, findings from previous studies in humans on the association between adolescent diet and breast cancer are inconsistent and self-reports of childhood diets may yield biased results. The DISC06 follow-up study explored the hypothesis that diet during adolescence may play a greater role in breast cancer risk than diet during adulthood by evaluating the longer-term effects of the DISC intervention during childhood and adolescence on subsequent biomarkers that have been associated with breast cancer risk in adults. Background Cardio-metabolic diseases (CMDs) include diabetes mellitus, cardiovascular disease, kidney disease and common risk factors that underlie these conditions such as central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension. CMDs are a growing global public health problem, with high mortality rates particularly in low- and middle-income countries. However, CMDs have the advantage of being predictable through identification of risk factors and also preventable through changes in lifestyle, particularly through healthy eating habits and regular physical activity. The greatest gains in prevention have been seen when early and target-driven interventions address multiple risk factors. However, achieving control of individual risk factors is poor, globally. Quality improvement schemes have shown promise in high-income countries, but were untested in South Asia at the time of these studies. In people of South Asian origin, diabetes, and CMD risk factors and events occur at younger ages and lower body mass indices when compared to other ethnic groups, and are rapidly increasing with socioeconomic and nutrition transitions. CVD is currently the leading cause of death in both urban and rural India. Prior to these studies, the major source of population level estimates of CMD risk factors, morbidity and mortality in India was ad hoc surveys. Such methods are limited by problems of sample design, lack of standardization, frequent measurement errors and incomplete reporting of results. A surveillance model of study would allow for more extensive comprehension of the distribution and trends of determinants and disease, dynamic integration of information from multiple sources, and aid in the development of safe, effective prevention and care models. Participants Protocol 1 Households within each study site were randomly selected. Any non-pregnant individuals permanently residing in the household and at least 20 years of age were eligible for enrollment. 4,943 participants from Chennai, 4,425 participants from New Delhi, and 4,016 participants from Karachi were enrolled in the first surveillance cohort. The study aimed to recruit 6,500 new participants at each of the three sites for the second cohort. Protocol 2 Eligible patients were at least 35 years of age with a diagnosis of diabetes, poor glycemic control (HbA1c ≥ 8.0%), and one or both of: dyslipidemia (LDL ≥ 130 mg/dl) or systolic hypertension (SBP ≥ 140 mmHg), irrespective of medication use. The study enrolled a total of 1,146 patients from ten clinical sites, with 575 randomized to the intervention group and 571 randomized to the usual care group. Protocol 3 Participants were recruited from 38 sub-centers in the Solan district located in the Indian state of Himachal Pradesh. All community members, aged 20 years or older and permanently residing in well-defined rural communities in the selected geographical areas, were eligible to participate. Design Protocols 1/3 The Solan Surveillance study was the rural counterpart of CARRS Surveillance study, and therefore they used similar methodology. The CARRS surveillance study was conducted in three sites: two in India (Chennai and New Delhi) and one in Pakistan (Karachi). The Solan Surveillance study was conducted in the Solan District of Himachal Pradesh, India. Recruitment occurred and data were collected via household surveys. While the primary study design for the surveillance model was cross-sectional, a cohort study design was used to follow-up the participants for three to four years subsequent to the initial cross-sectional study. Baseline surveys gathered information on demographic and socio-economic characteristics, presence of CMDs and risk factors, previous or existing target organ damage, female reproductive history, quality of life, disability, health care utilization, and quality and cost of care. Additional clinical measurements included blood pressure, pulse rate, mid-arm circumference, waist circumference, hip circumference, skinfold thickness, height, and body composition. Each surveillance study implemented a second independent cross-sectional survey several years after the first in order to estimate the trend in prevalence of CMDs and their risk factors. Outcomes of interest included anthropometric changes; incidence of new intermediate risk factors or changes in pre-existing risk factors such as dyslipidemia, hypertension, and diabetes; and morbidity and mortality associated with CMDs. Protocol 2 The CARRS Translational trial was a multi-site, individually randomized, controlled parallel group study that tested a comprehensive, multi-factorial CVD risk reduction intervention in type 2 diabetes patients attending established out-patient clinics in South Asia. The intervention strategies followed internationally accepted evidence-based CVD risk management algorithm-guidelines for individuals with diabetes, with adaptations to increase relevance to the South Asian population. The intervention utilized two major health care management strategies: (1) a web-enhanced decision-support software to store patient health records, provide automated decision-support prompts for patient management, and remind providers and participants of the guideline-recommended care processes, and (2) a non-physician care coordinator to facilitate care according to the CVD risk factor management guidelines, provide individualized follow-up according to baseline risk and compliance, empower and encourage patients to achieve management targets, and coordinate guidance from a multi-disciplinary team. The control group received the existing standard care existing at the clinical site. Potential participants were invited for two pre-randomization screening visits to assess history, anthropometry, blood pressure, heart rate, and to collect a fasting venous blood sample for glucose, HbA1c, lipid profile, creatinine, potassium, sodium, and ALT measurements. At the baseline/randomization visit, all participants underwent further assessments including a detailed history and physical examination, questionnaires (self-management, quality of life, treatment satisfaction, and cost of care), and preventive exams including urine analysis, electrocardiogram, and foot and eye examinations. Participants in the intervention group were scheduled for follow-up every three months, and participants in the control group were scheduled for yearly follow-up. Median follow-up was 28 months. The primary outcome was a sustained relative difference in those achieving multiple risk factor targets (glycemic and BP or lipid control, or both) in the intervention group, compared to the control group. Conclusions Protocol 1 Not available Protocol 2 Compared with usual care, intervention participants achieved larger reductions in HbA1c level and reported higher health related quality of life and treatment satisfaction. The multicomponent care management strategy improved achievement of diabetes care goals. Protocol 3 Not available

Study phs004776

NCTN: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL) (E1912)

Study ID: E1912NCT Number: NCT02048813 ECOG-ACRIN Cancer Research GroupSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL) (E1912)Trial Description: This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Clinical data presented in the following publication(s):PMID 31365801 PMID 34407545Disease type(s): Hematopoietic Neoplasm/Leukemia - Chronic Lymphoid LeukemiaClinical dataset(s) included:NCT02048813-D1 (PMID 31365801): There are three different datasets (-D1 through -D3) for ECOG-ACRIN trial E1912's primary publication, PMID 31365801. This dataset, NCT02048813-D1, contains baseline characteristics, stratification factors, IGHV mutation status, treatment, second primary cancer, and efficacy data. NCT02048813-D2 (PMID 31365801): There are three different datasets (-D1 through -D3) for ECOG-ACRIN trial E1912's primary publication, PMID 31365801. This dataset, NCT02048813-D2, contains grade 3 and above toxicity data as shown in Table 2 of the paper. NCT02048813-D3 (PMID 31365801): There are three different datasets (-D1 through -D3) for ECOG-ACRIN trial E1912's primary publication, PMID 31365801. This dataset NCT02048813-D3 contains worst grade, treatment-related toxicity data as shown in supplemental Table S7 of the paper. NCT02048813-D4 (PMID 34407545): There are two different datasets (-D4 and -D5) for ECOG-ACRIN trial E1912's publication, PMID 34407545, reporting on measurable residual disease and progression-free survival. This dataset, NCT02048813-D4, contains baseline characteristics, baseline leukocytes, thymidine kinase, and survival data for patients with MRD data that were not already included in NCT02048813-D1.NCT02048813-D5 (PMID 34407545): There are two different datasets (-D4 and -D5) for ECOG-ACRIN trial E1912's publication, PMID 34407545, reporting on measurable residual disease and progression-free survival. This dataset, NCT02048813-D5, contains longitudinal measurable residual disease 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 phs004233

Women's Health Initiative Clinical Trial and Observational Study-BioLINCC (WHI-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.Related Studies: This accession includes only deidentified phenotypic data. Related accessions for WHI include: WHI Cohort (dbGaP phs000200, and Women's Health Initiative Clinical Trial and Observational Study – Imaging (dbGaP phs003824), and Women's Health Initiative - Life and Longevity After Cancer (dbGaP phs004174).Available Data: Data are available from the following: the multi-component clinical trial (CT), the observational study (OS), the extension studies (ES), and the ancillary memory study (MS). Includes outcome data through 3/31/2018.Objectives: The clinical trial assessed the safety and efficacy of three interventions. Specifically, it evaluated (1) the major health benefits and risks of estrogen plus progestin and estrogen alone, (2) the effects of a low-fat eating pattern on risk of colorectal cancer, and (3) the efficacy of calcium with vitamin D supplementation for preventing hip and other fractures. The objective of the memory study was to determine whether estrogen plus progestin therapy protects global cognitive function, and evaluate the therapy's effect on the incidence of dementia and mild cognitive impairment.The observational study is examining the relationship between lifestyle, socioeconomic, health, and other risk factors with cardiovascular, breast cancer, colorectal cancer and osteoporotic fracture outcomes. Secondary objectives include providing more reliable estimates of the extent to which known risk factors predict disease, more precise estimates of new occurrences of disease, and to provide a future resource for the identification of new or novel risk factors especially factors found in blood. Background: The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing the major causes of death, disability, and frailty in postmenopausal women, specifically heart disease, cancer, and osteoporotic fractures. The WHI is primarily composed of an observational study (OS), as well a clinical trial (CT) with three components: Hormone Replacement Therapy (HT), Dietary Modification, (DM) and Calcium/Vitamin D supplementation (CaD).Prior to the WHI, observational studies suggested that postmenopausal hormone therapy was associated with a decreased risk of coronary heart disease (CHD). Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin. Observational studies primarily examining unopposed estrogen preparations have suggested a 30% to 50% reduction in coronary events, and an 8% to 30% increase in breast cancer with extended use. Other research findings indicated that hormone therapy was also associated with a decreased risk of osteoporosis and increased bone density. The WHI HT trials were designed to test the effects of postmenopausal hormone therapy on risk for coronary heart disease and assess overall risks and benefits in predominantly healthy women.The Women's Health Initiative Memory Program (WHIMS) consists of a suite of studies which include cohorts of women who participated in the WHI HT trials. Postmenopausal women have a greater risk than men of developing Alzheimer's disease, but studies of the effects of estrogen therapy on Alzheimer's disease have been inconsistent. Additionally, observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive.International comparisons and migration studies have suggested that countries with 50% lower fat intake than the US population had approximately one third the risk of colorectal cancer. Additionally, fairly consistent evidence existed for an effect of dietary fat, vegetables and fruits, and grains on colorectal cancer risk from within-country observational studies, although the protective effect of lower fat intake was no longer clear after adjusting for energy intake. The WHI DM trial was the first randomized trial to directly address the health effects of a low-fat eating pattern in predominantly healthy postmenopausal women from diverse racial/ethnic, geographic, and socioeconomic backgrounds.Osteoporosis is a major cause of injury, loss of independence, and death, and contributes to hip fractures. Observational evidence and data from previous randomized clinical trials suggest that calcium and/or vitamin D supplements may slow bone loss and reduce the risk of falls in postmenopausal and elderly women. However, evidence from trials, observational studies, and meta-analyses of calcium and vitamin D supplementation with respect to hip and other fractures was limited at the time the WHI was initiated. In two prior randomized trials, calcium plus vitamin D supplements did not reduce the risk of nonvertebral fractures among older women. When the WHI CaD trial was designed, guidelines recommended daily intakes of 800 to 1200 mg of calcium with 400 IU of vitamin D for the prevention of osteoporosis, which was not met by many American women. Therefore, the WHI CaD trial was designed to test the primary hypothesis that postmenopausal women randomly assigned to calcium plus vitamin D supplementation would have a lower risk of hip fracture and, secondarily, of all fractures than women assigned to placebo. Participants: A total of 68,132 women were randomized into at least one component of the clinical trial. 27,347 women were enrolled in the hormone therapy component with 16,608 in the estrogen plus progestin trial and 10,739 in the unopposed estrogen trial, 48,835 women were enrolled in the diet modification component, and 36,282 women were enrolled in the calcium/vitamin D component. 7,479 women 65 years of age and older at baseline and that participated in the HT trial component were enrolled in the ancillary memory study.Women who were either ineligible or unwilling to participate in the clinical trial component were enrolled in the observational study. For example, many potential participants to the clinical trial component of the study were already undertaking a low fat diet or were using hormone replacement therapy. The effect of the selection process was that women enrolled in the observational study tended to have healthier lifestyles compared to those enrolled in the clinical trial. In total, 93,676 subjects were enrolled in WHI OS, with over 16% being members of a racial/ethnic minority group.The first WHI Extension Study enrolled 115,407 consenting participants from all components of the original WHI study for an additional five years of follow-up, from 2005 to 2010. In 2010, 93,567 women consented to continued follow-up. Design: The clinical trial component of the WHI included three randomized comparisons: hormone therapy, dietary modification, and calcium/vitamin D supplementation. Women could have been randomized into one, two or all three trials.The hormone therapy trial enrolled women to one of two double-blinded trials: estrogen (0.625 mg of conjugated equine estrogens daily) plus progestin (2.5 mg of medroxyprogesterone acetate daily) or estrogen alone. Women with a prior hysterectomy were eligible for the trial of unopposed estrogen. Women with an intact uterus at screening were initially also eligible for unopposed estrogen, but were reassigned to the trial of combined postmenopausal hormones beginning in 1995. Both trials randomized participants 1:1 to either hormone therapy or placebo. A 3-month washout period was required before baseline evaluation of women using postmenopausal hormones at initial screening. Study participants were contacted by telephone 6 weeks after randomization to assess symptoms and reinforce adherence. Follow-up contacts by telephone or clinic visit occurred every 6 months, with clinic visits required annually.The estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years of follow-up because health risks, including increased risk of breast cancer and cardiovascular disease, exceeded benefits. The estrogen alone trial was stopped early in March 2004, because an increased risk of stroke was found with no benefit for coronary heart disease. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome.The dietary modification trial evaluated the effect of a low-fat, high fruit, vegetable, and grain diet on preventing cardiovascular disease and cancer. Participants were randomly assigned to an intervention or a comparison group in the ratio of 2:3 for cost-efficiency. The intervention was an intensive behavioral modification program, using 18 group sessions in the first year and quarterly sessions thereafter, led by specially trained and certified nutritionists. The program was designed to promote dietary change with the goals of reducing total fat to 20% of energy intake, increasing vegetables and fruits to at least 5 servings daily and grains to at least 6 servings daily. The intervention did not include total energy reduction or weight loss goals. Comparison group participants received a copy of the US Department of Health and Human Services' Dietary Guidelines for Americans and other health-related materials but were not asked to make dietary changes. Dietary intake was monitored using the WHI food frequency questionnaire at 1 year and in a rotating one-third subsample every year thereafter. Women completed a medical update questionnaire every 6 months, and medical records were sought for all women reporting colorectal cancer. The primary outcome was invasive colorectal cancer incidence.Participants in the calcium/vitamin D trial were randomized 1:1 to either supplements or placebo. Active tablets contained 500 mg of elemental calcium (as calcium carbonate) and 200 IU of vitamin D3, to be taken twice daily with meals. The presence and severity of symptoms, safety concerns, and outcomes were ascertained at annual clinic visits and telephone or clinic visits at intervening six-month intervals. Risk factors for fracture were assessed by questionnaire, interview, and clinical examination. The primary outcome was incidence of hip fracture.Participants in the observational study attended a baseline examination and were re-examined three years later. Participants completed annual updates of exposures and clinical outcomes by mail. Final data were collected by mail during the close-out period in April 2004 to March 2005. The major clinical outcomes of interest were coronary heart disease, stroke, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, osteoporotic fractures, diabetes, and total mortality. Most outcomes were initially ascertained by self-report on an annual questionnaire and documented by hospital and related records. Charts with potential cardiovascular, cancer, and fracture outcomes were sent to the local physician adjudicator for evaluation and classification. Staff at the Clinical Coordinating Center coded and adjudicated all cancers of major interest in the study using standardized SEER guidelines.In 2005, WHI participants were invited to join the Extension Study for an additional five years of follow-up in order to collect long-term outcomes. Participants completed annual data collection forms primarily by mail, similar to the OS follow-up. Women reporting study outcomes were contacted by WHI field center staff to obtain additional details and medical records, which were evaluated by physician adjudicators. In 2010, the woman remaining were invited to join the next Extension Study. In the second extension, women were divided into two groups, one of which would have outcomes documented with medical records (the Medical Records Cohort, MRC), and the other would just be followed by self-report (the Self-Report Cohort, SRC). The MRC consists of women who were in the hormone therapy trials, and all African-American and Hispanic women. In 2012-2013, a subset of the MRC was identified for a potential in-home visit to collect blood and several objective measures of physical functioning.Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin after an average 5.2 year follow-up among healthy postmenopausal US women (Rossouw et al., 2002, PMID: 12117397). Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo (Rapp et al., 2003, PMID: 12771113), increased the risk for probable dementia, and did not prevent mild cognitive impairment (Shumaker et al., 2003, PMID: 12771112). The use of conjugated equine estrogen increased the risk of stroke, decreased the risk of hip fracture, and did not affect CHD incidence in postmenopausal women with prior hysterectomy after an average of 6.8 years of follow-up (Anderson, et al., 2004, PMID: 15082697). Over approximately 8 years of follow-up, a low-fat dietary pattern did not reduce the risk of colorectal cancer (JAMA 2006;295:643-654). Calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density; however, no significant difference was observed in hip fractures (Jackson, et al., 2006, PMID: 16481635).

Study phs004266

NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study

NCCAPS is a longitudinal prospective cohort study designed to assess patient, disease and treatment factors associated with short- and long-term outcomes in patients with cancer who develop COVID-19. We also aimed to describe COVID-19 symptoms and treatments, and to describe disruptions in cancer treatment due to COVID-19. The study enrolled patients with cancer on active treatment or with a history of stem cell transplant or CAR-T cell therapy with new, active COVID-19, defined as being within 14 days of their first positive SARS-CoV-2 test. The study found that receipt of chemotherapy and baseline history of stroke, atrial fibrillation or pulmonary embolism were associated with a higher risk of hospitalization for COVID-19. Vaccination for SARS-CoV-2 was associated with a lower risk of hospitalization. Death due to COVID-19 was highest in patients with lymphoma, intermediate in those with acute leukemia and lung cancer, and lowest in those with other solid tumors and other hematologic cancers. Disruptions of cancer treatment were frequent in the first 30 days after SARS-CoV-2 infection.

Study phs004178

Uncovering Colorectal Cancer Etiology and Biology by Integrating Proteomics with Other Omics Data

This study included the expression profiling of approximately 10,000 proteins generated in normal colon tissue samples collected from 323 participants of European descent, paired with genome-wide genotype data obtained from blood samples. Using these proteomics and genotype datasets, we developed genetically prediction models for protein expression and conducted a proteome-wide association study (PWAS) of colorectal cancer (CRC) in European populations to identify proteins associated with CRC risk.

Study phs004089

The Somatic Mutational Landscape of Thyroid Cancer in Patients with Germline PTEN Mutations

PTEN hamartoma tumor syndrome (PHTS) is associated with a high rate of thyroid cancer and benign thyroid disease, yet nothing is known of the genomic landscape of PHTS-associated thyroid tumors. In this study, exome sequencing was performed on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS, sequenced in tumor-normal pairs. Somatic variant calling was utilized to determine the somatic mutational landscape of thyroid tumors in this population. This was then compared to the known mutational landscape of sporadic thyroid cancer in the general population using sequencing data from The Cancer Genome Atlas. The primary finding of the study was that PHTS-associated thyroid tumors had a unique genomic landscape, including a high frequency of second-hit somatic PTEN alterations compared to the sporadic thyroid tumors. Additionally, PHTS-associated thyroid cancers were found to have somatic alterations in BRAF, RAS family members, and genes associated with DNA double stranded break repair. Data available through dbGAP will include tumor BAM files for each tumor, normal BAM files for each patient, and MAF files for PHTS-associated thyroid cancer and PHTS associated benign thyroid nodules.

Study phs003640

Chromatin Accessibility Profiling Identifies a Stem Cell-Like Subtype of Small Cell Lung Cancer with Poor Prognosis

Eight-week-old male or female NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ; #005557, Jackson Laboratory) were subcutaneously implanted with fresh patient needle biopsies. Mice were monitored daily, with caliper measurements and body weights performed twice weekly. Once tumors reached the size limit (2000 mm³) or mice became moribund, the mouse was euthanized, and a 3x3 mm³ tumor fragment was transplanted into a new mouse (P2). This process was repeated to achieve a minimum of passage three (P3) for each patient-derived origin. ATAC sequencing on PDX samples was conducted using the high-throughput Illumina HiSeq 4000 system. The same biopsy samples used for ATAC-seq were utilized for RNA-seq library preparation and sequencing, following the Illumina HiSeq protocol (NCI CCR Sequencing Facility). The study identified the stem cell subtype within Small Cell Lung Cancer (SCLC) cases and identified the gene signature associated with stemness behavior., which were validated in independent limited and extensive stage patients dataset.

Study phs003983

Kids First: Genomics of Isolated Cleft Lip

Isolated Cleft Lip (CL, Human Phenotype Ontology # HP0100335) is a subtype within Orofacial Clefts (OFC, HP0000202) birth defects. OFCs can involve gaps in the lip, alveolus and/or the hard or soft palate. Developmental origins of the affected structures, epidemiology, and familial patterns of CL versus other OFCs suggest some common risk factors, but emerging evidence emphasizes that these subtypes also have unique risk factors. Isolated CL has seldom been investigated separately in genetic studies. Early studies using microsatellite markers prior to the availability of SNP chips found differences in CL families versus other cleft subtypes, notably reporting increased association with certain IRF6 variants in CL families versus other cleft types. With the advent of SNP chips, some studies addressed CL, e.g. genome-wide association of CL was seen with TPM1 and NOG and 9q21.32. We have performed some of the only genome-wide association studies (GWAS) to compare and contrast CL and Cleft Lip with Cleft Palate (CLP). We find evidence that CL and CLP have some distinct genetic risk factors, differences in strength or direction of effects between CL and CLP, and modifying loci that predispose specifically for CL over CLP. Some loci are most-significant in families where all affected members had CL. Modifiers of cleft lip laterality and side of the cleft were more successful in CL than in CLP and the loci identified in CL had no detectable effect in CLP, reinforcing the idea that CL and CLP have distinct risk factors. An overall conclusion from these studies is that CL appears more genetically homogeneous than does CLP, thus highlighting the importance of subtype and family type inclusion in studies of OFCs. Importantly, the homogeneity of CL makes it more amenable to gene discovery in the moderate sample sizes available with whole genome sequencing (WGS). The current project builds upon the GWAS and WGS analyses by our group and others. The WGS data generated will be used to discover new loci for CL, to replicate/prioritize previously published loci, and to aid in determining CL-specific causal genes/alleles. Short Read WGS data available for 1903 individuals include 629 affected probands: 553 CL and 40 CLP (with CL relatives) complete trios, 29 CL and 1 CLP dyads, and 5 CL and 1 CLP singletons. Of the 1903 total individuals, 554 are of European descent, 381 Central/South American descent, 857 of Asian descent, 7 of African descent, and 104 are race other/unknown. With our phenotypic data plus the WGS, we will be able to find new loci, gain better understanding of how risk related to those loci differs across populations, create the knowledge needed to choose loci for follow-up functional studies, build the knowledge needed for accurate risk predictions, and ultimately set the stage for translation into clinical practice. Study Population: The individuals and families utilized in this project were recruited through the Pittsburgh Orofacial Cleft study (POFC) involved research collaborations world-wide coordinated by the Center for Craniofacial and Dental Genetics of the University of Pittsburgh (CCDG). Extensive information is available for many of these trios, including sex, self-reported race and ethnicity, birth date and age at enrollment, phenotypes for affected cases (i.e. extensive detail on the OFC defect in terms of type, laterality, completeness), phenotypes for all affected and unaffected family members (including facial measurements, lip morphology, dental characteristics and many more), vital status and age at last known vital status, clinical information (e.g. surgical and medical history for all affected cases, some limited systems review for unaffected family members), and family medical history (e.g., family history of cancer and birth defects).Molecular Technology: Short Read WGSData Available: Demographics (site, age, sex, race, ethnicity) Cleft details Family level cleft details (i.e. multiplex, clefting maternal side, clefting paternal side, or both) Height/Weight Pregnancy Exposures data (birth height, birth weight, smoking, vitamins, alcohol, epilepsy, gestational diabetes) for 3 months prior to first trimester and first trimester. Subject_IDs from other sequencing studies Data use limitations from the consents The remaining phenotypic/medical/image data for this study are available through FaceBase (facebase.org): DOI: 10.25550/5A-FJBJ and DOI: 10.25550/56-ES6P.

Study phs003893

Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor

Immune checkpoint inhibitors (ICIs) are widely used in anti-cancer therapies, but they can cause morbid and potentially fatal immune-related adverse events (irAEs), such as ICI-related myocarditis (irMyocarditis). The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood in irMyocarditis patients and controls by leveraging single‐cell RNA sequencing (scRNA‐seq) coupled with T-cell Receptor Sequencing (TCR-Seq). Our analysis demonstrated increased frequencies of cytotoxic T cells, inflammatory mononuclear phagocytes (MNPs), conventional dendritic cells (cDCs), and inflammatory fibroblasts in irMyocarditis heart tissue. Additionally, we revealed decreased frequencies of plasmacytoid dendritic cells, cDCs, and B lineage cells but an increased frequency of MNPs in the blood of irMyocarditis patients. Raw data for heart and blood can be found in dbGaP. All processed data and raw TCRseq data from heart tissue and tumor samples for this study can be found in GEO (Accession number GSE228597).Subject IDs with the prefix "SIC" were collected by the Severe Immunotherapy Complications (SIC) service at MGH due to suspicion of immune-related adverse events. Subject IDs with the prefix "donor" were collected by the MGH Melanoma Biobank at scheduled timepoints; this biobank systematically collects samples from patients at MGH at clinically relevant timepoints.

Study phs003413

Detroit Research on Cancer Survivors (ROCS) and Disparities and Cancer Epidemiology - Colorectal Cancer (DANCE)

The goals for this study were as follows:1. Enroll a total of 5,060 African Americans newly diagnosed with cancer into the Detroit Research on Cancer Survivors (Detroit ROCS) Cohort. These population-based cases will be ascertained through the Detroit Metropolitan Detroit Cancer Surveillance System (MDCSS), a founding member of the NCI SEER Program. Participation at baseline will include a written, web-based, or telephone interview, saliva and/or blood collection, and tumor block retrieval, with detailed cancer-related information coming from the MDCSS registry and medical records.2. Enroll a subgroup of colorectal cancer patients identified through the Louisiana Tumor Registry (LTR). An additional 500 colorectal cancer patients, approximately half non-Hispanic white and half African American, will be identified through the LTR and enrolled into the ROCS protocol. The survey is the same survey administered to the ROCS cohort. The Louisiana (“DANCE-CRC”) cohort will not be followed beyond baseline, and blood will not be collected (tumor tissue, however, will be collected, deidentified, and sent for processing through Dr. Rozek's laboratory at Georgetown University).The proposed cohorts will provide for a broad research agenda evaluating cancer outcomes in African Americans across a variety of factors from individual, provider, health care system and community perspectives. These factors include tumor characteristics driving individualized treatment planning, quality of life after a diagnosis and recurrence. Utilizing the MDCSS registry, we will enroll a large population-based sample of African-American cases with lung, breast, colorectal, and prostate cancers and their caregivers resulting in a cohort that will provide substantial benefit to the cancer research community. KCI has a strong history of research in the African-American community and the faculty represents a breadth of experience that includes clinical oncology, genetic epidemiology, environmental exposures, quality of life, treatment decision making, racism/discrimination, and health behaviors. Drs. Schwartz and Beebe-Dimmer have been and will continue to be generous collaborators with other institutions to ensure that this resource will be extensively utilized. The proposed overall cohort will be the only one of its kind, to our knowledge, filling a substantial gap in our understanding of the determinants driving cancer outcomes in African Americans. In addition to registry data detailing cancer specifics, yearly surveys have collected information about individualized treatment experiences, heath histories, family histories, quality of life after a diagnosis, recurrence and caregiving. Population: Adult cancer survivors (see inclusion criteria in next section) Molecular Technologies: Genotyping: Infinium Expanded Multi-Ethnic Genotyping Array (MEGAEX) DNA Sequencing: Illumina NovaSeq X Plus using XLEAP-SBS (sequencing by synthesis) Whole genome sequencingPrincipal Findings: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Variants in DNA damage repair genes and HOXB13 may be important cancer risk factors for Black men diagnosed with prostate cancer, and are more frequently observed in men with a family history of cancer. ROCS participants reported high rates of a family history of cancer. The high rate of eligibility for Cancer genetic counseling among ROCS participants supports the need for interventions to increase referrals and uptake of genetic counseling among African Americans 60% of ROCS participants reported participating in regular physical activity (PA), with 24% reporting ≥150 min/wk. There were no differences by sex, but prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely. Survivors who reported participating in regular PA reported higher health-related quality of life and lower depression. More African American than White survivors reported financial hardship and limiting care. More White than African American survivors reported utilizing assets, while more African American survivors reported cancer-related debt. Data available in dbGaP: Individual phenotype data Individual genotype data Individual sequencing dataSample types: Germline DNA

Study phs003116

An Ultrasensitive Method for Detection of Cell-Free RNA

Our study describes the development of a novel method for cell free RNA (cfRNA) analysis called RARE-Seq (Random priming & Affinity capture of cell-free RNA fragments for Enrichment analysis by Sequencing). We find RARE-Seq improves the limit of detection for tumor-naïve cancer detection while maintaining high specificity. We explore the potential utility of RARE-Seq in diverse clinical applications, including non-invasive ctRNA genotyping, treatment resistance monitoring, and molecular characterization of non-malignant conditions.

Study phs004091

Interdisciplinary Approaches for Understanding how Arsenic and Micronutrients Affect the Epigenome to Influence Spina Bifida Risk

This hospital-based case-control study was conducted in Bangladesh between December 2016 and December 2022 to investigate the association between environmental arsenic exposure and the risk of spina bifida. The study enrolled children with spina bifida (cases) and unaffected children (controls), along with their biological parents. Cases included infants under one year of age with clinically confirmed diagnoses of myelomeningocele or meningocele at the National Institute of Neurosciences & Hospital (NINS). Controls were frequency-matched on age and recruited from the same catchment area through NINS and Dhaka Shishu Hospital. Children with conditions potentially related to arsenic exposure, such as keratosis or cancer, were excluded from the control group. A small subset of case families were reclassified as controls following surgical reevaluation and a revised diagnosis of lipomeningocele, then later removed from the control group. They are no longer assigned to either the case or control category in the datasets. Saliva samples were collected from children and parents using Oragene® kits and stored at room temperature before shipment to Boston, MA, USA. DNA extraction was carried out with the Maxwell® RSC Buccal Swab DNA kit. A total of 749 saliva DNA samples, representing 713 unique individuals and 36 replicates, were shipped to the Broad Institute for analysis. Samples were randomized across Illumina Global Screening Array (GSA) chips to minimize batch effects. The primary molecular technology employed in this study was the Illumina Global Screening Array (GSAMD-24v1-0), which includes approximately 688,000 genetic markers. Data generated include raw and processed genotype files as well as a comprehensive quality control report. The genotyping dataset available through dbGaP will consist of genotype calls from spina bifida cases, controls, and their parents, along with associated demographic, clinical, and exposure metadata, enabling future analyses of gene-environment interactions in the context of neural tube defect risk.

Study phs003733

Real-Time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole exome sequencing (WES) and RNA-sequencing (RNA-Seq) for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAP-kinase pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.

Study phs001652

APOBEC Mutagenesis, Kataegis, Chromothripsis in EGFR-Mutant Osimertinib-Resistant Lung Adenocarcinomas

Expanding on studies investigating apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, it has been hypothesized that mutational signature analysis may help better understand acquired resistance to targeted therapies. Using mutational signature analysis in Receptor Tyrosine Kinase (RTK) driven lung adenocarcinomas, more specifically EGFR mutant lung cancer, APOBEC dominant mutational signatures were noted more frequently in subclonal post Tyrosine Kinase Inhibitor (TKI) treatment biospecimen samples and in the presence of large-scale genomic rearrangements. This is hypothesized to be due to the pressure of treatment with TKIs; a fact that should be further explored and can be potentially manipulated in order to overcome drug resistance.

Study phs003812

scRNA-seq of Multiple Myeloma and Tumor Microenvironment Cells from Bone Marrow During CAR T-Cell Therapy

Multiple myeloma (MM) is a treatable, yet incurable, plasma cell malignancy for which molecular mechanisms driving the development of therapy resistance remain largely elusive. To better characterize tumor intrinsic and immune tumor microenvironment (iTME) factors associated with CAR T-cell efficacy, scRNAseq (10x Genomics V3.1) was performed on purified MM cells (CD138+) and associated iTME cells (CD138- mononuclear cells) from fresh bone marrow aspirates harvested prior to therapy in 13 patients treated at Moffitt Cancer Center. After biopsy, 7 of these patients were treated with ABECMA (idecabtagene vicleucel or ide-cel) and 6 were treated with ciltacabtagene autoleucel (cilta-cel or CARVYKTI®). Bone marrow biopsies were collected between 2021 and 2023. In addition to the molecular data, demographic information for the samples is provided. These data allow for the assessment of transcriptional signatures at the single-cell level in both the tumor and its bone marrow iTME, associated with CAR T-cell therapy in MM patients.

Study phs004878

Genome Sequencing of Individuals with PTEN Hamartoma Tumor Syndrome

This study investigated genomic modifiers of cancer and neurodevelopmental outcomes among individuals with PTEN hamartoma tumor syndrome (PHTS), a rare hereditary disorder caused by germline PTEN variants and associated with broad clinical variability, including cancer predisposition, autism spectrum disorder, developmental delay, and intellectual disability. The primary aim was to determine whether additional inherited genomic variation beyond PTEN contributes to divergent clinical manifestations, particularly the development of cancer versus neurodevelopmental disorders.The main analytic cohort consisted of 543 probands with germline PTEN variants, including participants with cancer, neurodevelopmental disorders, both cancer and neurodevelopmental disorders, or neither phenotype at the time of consent.Molecular data were generated from germline DNA extracted from peripheral blood leukocytes using PCR-free whole-genome sequencing at approximately 30× coverage. Sequence reads were aligned to the hg38 human reference genome, followed by standard variant calling, quality control, annotation, and downstream genomic analyses. The study evaluated pathogenic or likely pathogenic variants in established cancer predisposition genes and neurodevelopmental disorder genes, and also performed genome-wide common-variant and rare-variant association analyses to identify candidate modifier loci.Principal findings showed that a subset of individuals with PHTS carried additional germline variants in known cancer- or neurodevelopment-related genes. Specifically, additional cancer-associated variants were identified in 37 of 543 probands, most commonly involving MITF, DICER1, and BRCA2, while neurodevelopment-associated variants were identified in 43 of 543 probands, including variants in DHCR7, POLG, ARSA, and other genes. Genome-wide analyses further identified candidate modifier loci with potential biological relevance to PTEN signaling and phenotype divergence, including ZNF713, TPTE2P1, and PDPK1. These findings support the hypothesis that PHTS clinical outcomes are influenced not only by germline PTEN variation, but also by additional inherited genomic modifiers.Data to be made available through dbGaP will include de-identified individual-level germline whole-genome sequencing data and associated phenotype information relevant to PHTS, cancer status, neurodevelopmental status, demographic variables, and PTEN variant classification, consistent with participant consent and institutional certification. The individual-level data are intended for controlled access.

Study phs004787

A Personalized Neoantigen Vaccine Generates Anti-Tumor Immunity in High-Risk Renal Cell Carcinoma

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumor, and result in clinical activity are largely unknown, particularly in patients with lower mutation burden tumors. We conducted a phase I trial testing a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV), with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months from surgery, none of the 9 initial participants experienced a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against PCV antigens, including RCC driver mutations in VHL, PBRM1, BAP1, KDM5C, and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones, and T cell reactivity against autologous tumor was detected in 7 of the 9 patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations, and induce anti-tumor immunity. These observations, in conjunction with the absence of recurrence in all 9 vaccinated patients, highlights the promise of PCV as effective adjuvant therapy in RCC. We are submitting whole exome sequencing (WES) data from whole blood samples and tumor FFPE samples, and RNA-Seq data from tumor FFPE samples. We are also submitting RNA-Seq data from purified tumor samples. Single-cell RNA sequencing (scRNA-seq) data will be submitted for skin samples (vaccine site biopsies at weeks 0, 4, and 13), tumor samples (including resected metastatic tumor samples for two patients), and normal kidney samples. Bulk T-cell receptor sequencing (TCR-seq) data will be submitted for blood samples.

Study phs003710

Single-Cell RNA-Sequencing of Human Prostatectomy Tissue

The tissue microenvironment in prostate cancer is profoundly altered. How prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) to assess the transcriptional profiles of the tissue microenvironment in prostate tissues from prostatectomies from men diagnosed with prostate cancer. For each subject, benign-enriched and tumor-enriched tissues were collected from the peripheral zone of the prostate. Additionally, to understand zone-specific differences of the prostate, benign tissues were also collected from the transition and central zones.

Study phs003480

Genomic Alterations and Transcriptional Phenotypes in Circulating Tumor DNA and Matched Metastatic Tumor

We analyzed a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent small cell lung cancer. We conducted cfDNA low-pass whole genome sequencing (0.1X coverage) and exome sequencing (130X coverage) in comparison with time-point matched tumor characterized using whole-exome (130X) and transcriptome sequencing. A direct comparison of cfDNA and tumor biopsy revealed that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor, but also identifies clinically relevant resistance mechanisms and cancer driver alterations not detected in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Sequencing coverage of plasma DNA fragments around transcription start sites showed distinct treatment-related changes and captured the expression of key transcription factors n the corresponding SCLC tumors.

Study phs003689

Women's Health Initiative (WHI) - Life and Longevity After Cancer (LILAC) (WHI-LILAC-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: The LILAC substudy was initiated to collect information on cancer treatment and long-term outcomes in women diagnosed with eight selected cancers during their participation in WHI.Background: Improvements in early detection and treatment have led to a surge in the number of cancer survivors in the United States creating a demand for a better understanding of their health concerns. Cancer survivor health concerns are diverse and complex due to the heterogeneity among individuals, cancer type, and treatment variability. To effectively examine these concerns, new resources need to be developed, including a much more comprehensive assessment on a large sample with longer-term follow-up than is typically available in cancer clinical trials. The WHI cohort, which is a large study with long-term follow-up, continues to be a good resource to study issues related to aging and health. The LILAC substudy was initiated with WHI participants who had been diagnosed with cancer to examine cancer survivorship among older women.Participants: Participants with no cancer (other than non-melanoma skin cancer) prior to enrollment in WHI and a confirmed invasive cancer diagnosis during WHI follow-up of one of the eight selected cancers were eligible for LILAC.A total of 9934 WHI participants living with cancer were eligible. Of those, 7751 consented and returned the baseline survey. This included 821 participants with melanoma, 781 participants with colorectal cancer, 648 participants with endometrial cancer, 397 participants with lung cancer, 4173 participants with breast cancer, 442 participants with non-Hodgkin lymphoma, 181 participants with leukemia, and 208 participants with EOC (which includes ovarian, fallopian tube and primary peritoneal cancers). Design: Participants still in active WHI follow-up who were eligible for the LILAC substudy were sent an invitational mailing that included a baseline survey. Baseline surveys collected data on initial cancer treatment, symptoms after treatment completion, and quality of life. WHI participants who consented to the LILAC substudy were subsequently sent annual surveys. Annual surveys collected any updates on treatment, as well as other topics related to cancer survivorship such as social support. Additional treatment information was obtained from Medicare claims and medical records.Conclusions: The LILAC substudy provides a resource for studying cancer survivorship among older women diagnosed with eight selected cancers.

Study phs004174

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