EGAS00001002471-sc-20190103 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001004547 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:All normal somatic cells are thought to acquire mutations but understanding of the rates, patterns, causes and consequences of somatic mutation in normal cells is limited. Uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands from women aged 19 to 81 years showed them to be clonal cell populations derived from recent common ancestors, with total mutation burdens that increase with age at ~29 base substitutions/year and which are many-fold lower than endometrial cancers. Normal endometrial glands frequently carry driver mutations in cancer genes. Driver mutation burdens increase with age and correlate negatively with parity. Phylogenetic trees of normal endometrial glands constructed using whole genome sequences indicated that clones with drivers often originate during the first decades and spread to colonise the endometrial epithelial lining. The results show that driver mutation landscapes differ between normal cell types, perhaps shaped by differences in normal tissue physiology, and suggest that the procession of neoplastic changes leading to endometrial cancer is initiated early in life.
| EGAD00001005214 | EGA
Project description:To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we conducted whole-exome and whole-genome sequencing for 56 endometrial glands and matched blood samples from 4 women. By collecting endometrial glands from different parts of the endometrium, we showed that multiple glands with the same somatic mutations occupied substantial areas of the endometrium.
| EGAS00001005822 | EGA
Project description:<p>Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding <em>Tet2</em> mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to <em>Tet2</em> mutation. Cell differentiation stage also influenced <em>Tet2</em> mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include <em>Sox4</em> that sensitized cells to <em>Tet2</em> inactivation, inducing dedifferentiation, altered metabolism and increasing the <em>in vivo</em> clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.</p>
1970-01-01 | MTBLS9914 | MetaboLights
Project description:Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases POLE and POLD1 replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
| EGAD00001006212 | EGA
Project description:<p>The purpose of the original study was to search for somatic mutations in the tyrosine kinome of serous and clear cell endometrial carcinomas (human). The study was conducted in two phases.</p> <p>Phase 1: A mutation discovery screen, in which ~577 exons encoding the catalytic domains of 86 tyrosine kinases were PCR-amplified and bidirectionally Sanger sequenced from 24 serous, 11 clear cell, and 5 mixed histology endometrial tumors. This was followed by alignment of sequence reads to the human reference sequence and subsequent nucleotide variant calling to identify potential somatic (tumor-specific) mutations. Potential somatic mutations were confirmed by re-amplification and sequencing of the relevant tumor DNA as well as matched non-tumor ("normal") DNA from the same case.</p> <p>Phase 2: A mutation prevalence screen, in which the non-catalytic regions two tyrosine kinase genes, TNK2 and DDR1, were PCR-amplified and sequenced from the 40 discovery screen tumors, and all coding exons of TNK2 and DDR1 were PCR-amplified and sequenced from another 10 clear cell, 21 serous, and 41 endometrioid endometrial tumors, in an effort to identify additional somatic mutations in each gene. Exons encoding the exonuclease domain of POLE were also sequenced to document somatic mutations.</p>
| phs000841 | dbGaP
Project description:DNA methyltransferase 3A (DNMT3A) is the most frequently mutated gene in clonal hematopoiesis (CH) and serves as a key tumor suppressor in the hematopoietic system. Somatic mutations in DNMT3A arise in hematopoietic stem and progenitor cells (HSPCs) many years before malignancies develop, but how they prime cells for transformation remains unknown, partly due to our inability to compare mutant to equivalent wild-type cells before frank disease. To overcome this challenge, we derived multiple normal and DNMT3A-mutant lymphoblastoid cell clones from a germ-line mosaic individual in whom these cells co-existed for nearly six decades. Although arising early in gestation, mutant cells dominated the blood, but not other tissues. Deep sequencing revealed similar mutational burdens and mutational signatures across normal and mutant clones. In contrast, epigenetic profiling uncovered focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSPCs and with those present in leukemia samples. These results suggest that DNMT3A is responsible for maintaining a conserved DNA methylation pattern that is maintained for decades and across cell types and states. Erosion of this pattern confers a distinct competitive advantage, increasing the likelihood of malignant transformation
2020-07-15 | GSE150515 | GEO
Project description:With aging, normal human tissues experience expansion of somatic clones that carry cancer mutations. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, from whole exome sequencing of 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of ulcerative colitis patients. The affected epithelium accumulates somatic mutations in multiple IL-17 signaling-related genes, including NFKBIZ, ZC3H12A, and PIGR, which are rarely identified in colon cancer. Targeted sequencing validates pervasive spread of IL-17 signaling-related mutations. Unbiased CRISPR-based knockout screening in colon organoids illuminates mutation-mediated resistance to IL-17A-induced proapoptotic response. Some of these genetic mutations are known to exacerbate experimental colitis in mice, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a unique genetic landscape adapting to a hostile microenvironment and its potential contribution to the pathogenesis of ulcerative colitis.
2019-10-21 | GSE127757 | GEO
Project description:The objective of the study is the provide proof of high correlation between somatic and germline mismatch repair instability. This correlation is specifically researched in an area where patients have less access to cancer education and genetic testing for various reasons such as lack of insurance and general accessibility.
The study concentrates on early diagnosis of Lynch syndrome. Lynch syndrome is usually diagnosed from a blood test resulting in a mutation of one of the mismatch repair genes. Those are MLH1, MSH2, MSH 6, PMS2. A mutation in one of these genes creates a mismatch repair instability,hence higher incidence of cancers in specific organ groups. Amongst these organs are the Uterus, Ovaries, Upper genitourinary system, Pancreas and GI system.
The most common endometrial carcinoma which is found in Lynch syndrome is of endometrioid histology. Most patients with known germline mismatch repair instability, have the same somatic mutation. Our study is looking into correlating somatic mutation to germline mutation.
By doing so, patients diagnosed with somatic mismatch repair instability will be also diagnosed with lynch syndrome without germline genetic testing.
Screening programs will be utilized earlier and preventive procedures offered.
Due to less access to educational programs, genetic counseling and testing in underserved areas, patients are sometimes lost to follow up. Our study seeks to prove high correlation between somatic and germline mutations and by doing so, patient will be diagnosed with Lynch syndrome straight after endometrial cancer staging. As a result, increased compliance will be expected and patients will be offered the recommended preventative surgeries and screening protocols.
| 2349042 | ecrin-mdr-crc
Project description:<p>International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (<strong>Mutographs</strong>) associated with this study are available in the <strong>European Genome-Phenome Archive</strong>: https://ega-archive.org/datasets/EGAD00001012223.</p>
2024-03-26 | MTBLS9394 | MetaboLights
Project description:This SuperSeries is composed of the following subset Series: GSE17816: Somatic Mutation Screen of Clear Cell RCC I GSE17818: Somatic Mutation Screen of Clear Cell RCC II Systematic somatic mutation screening of 4000 genes in human clear cell renal cell carcinoma. Information on corresponding somatic mutations in each sample can be found at http://www.sanger.ac.uk/genetics/CGP/Studies/.
2010-05-16 | E-GEOD-17895 | biostudies-arrayexpress