The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.
PALMO (Platform for Analyzing Longitudinal Multi-omics data) is a platform for analyzing longitudinal data from bulk as well as single cell. It allows to identify inter-, intra-donor variations in genes over longitudinal time points. The analysis can be done on bulk expression dataset without known cell type information or single cell with cell type or user defined groups. It allows to infer stable and variable features in a given donor and each cell type or a user defined group. The outlier analysis can be performed to identify technical/biological perturbed samples in a donor or a participant. Further, differential analysis can be performed to decipher time-wise changes in gene expression in a cell type. The data that is available in the dbGaP is the demo longitudinal samples used in the study, which includes hashed raw fastq files for single-cell RNA-sequencing (scRNA-seq) and non-hashed fastq files for single-cell ATAC-sequencing (scATAC) experiment.
Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1-year of treatment or exceptional cases of complete response to trastuzumab for ≥ 10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NR)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P=0.07), while more significantly pronounced in copy number gains (P=0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within chr8 (P=0.02) and in chr17 (P=0.06) and conferred a statistically significant benefit in overall survival.
This study was designed to develop methods that address the privacy risk associated with genetic variants obtained from genomic sequencing experiments. The preponderance of readily available genetic sequencing experiments has enabled the generation of datasets whose target purposes range from the genotyping of individuals for medical and forensic analyses, to the acquisition of molecular information for biological model development. However, by virtue of the experimental procedure, the raw sequences are tagged with small bits of patients' private variant information. In addition, depending on the protocol, these experiments may identify sequences from exogenous species. Raw human and microbial sequences can be analyzed as a whole to learn both general facts about biology, but can also be used to determine sensitive information about an individual. This presents a privacy conundrum for data sharing.To address privacy concerns, we have developed several mathematical and computational approaches to quantify the risk of disclosure of sensitive information from genetic sequence data, and to sanitize the associated reads in a manner that optimally maintains the utility of the data. In addition, we have generated environmental samples containing genetic information from consented individuals to evaluate the risk posed by such data. These samples were then used to assess the efficacy of the computational methods. Human-derived and -associated samples that are damaged or obscured by environmental factors represent the scope of samples used for experimentation in this study. Samples include, but were not limited to, swabs of contacted objects and glass slides coated in saliva from consented individuals. Blood samples were also acquired from the same consented individuals to create gold-standard comparison datasets.
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. Subjects: Postmenopausal women ages 50 to 79 were eligible to participate. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (12 months for women under 55 years of age), had had a hysterectomy, or had ever used postmenopausal hormones. Recruitment was carried out in 40 US clinical centers in 1993-1998. The clinical trial components had additional specific inclusion or exclusion criteria.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 (Beresford, et al., PMID: 16467233). 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). A recent review summarizes the conclusions from the WHI clinical trials with a focus on clinical practice (Manson, et al., 2024, PMID: 38691368).Description of ECG Imaging Data: Electric cardiograms (ECGs) were given to all clinical trial participants at baseline and in years 3, 6, and 9 of the original WHI study.EKG data consist of 12 lead 10 seconds ECGS sampled at 500Hz via GE ECG machines and process via GE MUSE system. The ECG waveform were directly exported from GE MUSE using MUSE export function in XML format, which include EKG waveform data as well as other ECG characteristics. Waveform data is in base64 encoded format, when it is decoded, it is a binary data that can be used to draw waveform graph. Many programming languages and data tools have built in functions to decode base64 strings. All the other necessary information is included in the LeadData section, total byte size, total sample size etc. (usually 1 sample is 2 bytes). See example below: encoded-data (base64 encoded string) JwAoAC0AKAAiACIAJAAkACQAIwAiACIAHgAcABwAGwAZABgAGAAYABcAEwAQABAAEAAL^/AAsADAAM... decoded-binary-data (1 sample is 2 bytes) 270028002D002800220022002400240024002300220022001E001C001C001B00 1900180018001800170013001000100010000B000B000C000C000D000D000D00 0A000A000A0009000600040004000700070005000500020... These binary values are integers (Y axis data of the graph), hence it is a straightforward process to draw the waveform graph. Acquisition dates have been redacted from this ECG data to comply with WHI policy. All acquisition dates within files and in file names have been set to January 1, 1900 (19000101) to comply with this policy.
The objectives of this project are the identification of markers related to cancer therapy resistance in the blood of breast cancer patients and to study the genetic changes in cancer cells during this development of resistance. Whole genome amplified DNA from Circulating Tumor Cells (CTCs), selected during the course of systemic treatment from blood of metastatic breast cancer patients, will be exome sequenced . The patients selected for this study did not respond to therapy.
Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data.
The Cooperative Study of Sickle Cell Disease was initiated in 1977 to determine the natural history of sickle cell disease (SCD) from birth to death in order to identify those factors contributing to the morbidity and mortality of the disease. Specific objectives included: 1) to study the effect of sickle cell disease on growth and development from birth through adolescence 2) to study the conditions or events that may be related to the onset of painful crises 3) to obtain data on the nature, duration, and outcome of major complications of SCD 4) determine the nature, prevalence, and age- related incidence of organ damage due to SCD, and 5) study the role of SCD and its interaction with selected health events.Phases 2 and 3 of the study involved followup of the infant cohort. A total of 709 infants (age less than 6 months) were enrolled during Phase 1 of the Cooperative Study of Sickle Cell Disease (CSSCD), and Phases 2 and 3 of the CSSCD was designed to follow these children for an additional 10 years. The study objectives included: 1) define prospectively the natural history of sickle cell disease; 2) determine the relationships between cognitive and academic functioning and brain status as determined by MRI; 3) determine the cognitive or behavioral markers of silent infarct; 4) determine the relationship of family functioning on the Family Environment Scale (FES) to brain status, cognitive functioning, and social and demographic factors; 5) continue studies that will enhance the state of knowledge on the influence of sickle cell disease on the psychosocial adjustment of children and adolescents. Phase 2A of the study sought to examine the progression of organ damage in the heart, lung, kidney, and liver in adult cohort patients (born before 1/1/56) enrolled in phase 1 of the study between 3/79 and 5/81. A total of 620 patients from 11 centers were eligible for phase 2A.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.
The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The Specific Aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping Aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.
One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p<0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex, and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. Conclusively, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed recurrent mutations of MYO5B in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis.
