Familial Melanoma Sequencing
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001000017 | EGA |
REPOSITORIES: EGA
Publications
POT1 loss-of-function variants predispose to familial melanoma.
Robles-Espinoza Carla Daniela CD Harland Mark M Ramsay Andrew J AJ Aoude Lauren G LG Quesada Víctor V Ding Zhihao Z Pooley Karen A KA Pritchard Antonia L AL Tiffen Jessamy C JC Petljak Mia M Palmer Jane M JM Symmons Judith J Johansson Peter P Stark Mitchell S MS Gartside Michael G MG Snowden Helen H Montgomery Grant W GW Martin Nicholas G NG Liu Jimmy Z JZ Choi Jiyeon J Makowski Matthew M Brown Kevin M KM Dunning Alison M AM Keane Thomas M TM López-Otín Carlos C Gruis Nelleke A NA Hayward Nicholas K NK Bishop D Timothy DT Newton-Bishop Julia A JA Adams David J DJ
Nature genetics 20140330 5
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function ...[more]
Similar Datasets
Project description:Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and SNP arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g. PARP1, CDKN2A) or co-segregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare co-segregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
2016-12-01 | GSE85010 | GEO
Project description:Rare germline variations in familial melanoma
| PRJNA335673 | ENA
Project description:Background: Familial melanoma accounts for 10% of cases, withCDKN2A being the main high-risk gene. However, the mechanisms underlying melanomagenesis in individuals at high risk of developing melanoma remain poorly understood. Objective: To analyze the transcriptome of melanocyte/keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to comprehend melanoma development. Methods: Primary melanocyte-keratinocyte co-cultures were established from healthy skin biopsies from 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and from 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. Results: We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P < 0.05). In addition, the PPI network analysis revealed a network that consisted of double stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes and regulation of chromosome segregation. The hub gene was BRCA1. Conclusion: The constitutive deregulation of BRCA1 pathway genes and immune response in healthy skin could be a mechanism related with melanoma risk.
2022-11-02 | GSE160902 | GEO
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
2019-01-01 | GSE109207 | GEO
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
2019-01-01 | GSE109206 | GEO
Project description:Background and Aims: Evidence for a genetic contribution to eosinophilic esophagitis (EoE) exists from family and genome-wide association studies. Extensive investigation into rare variants contributing to EoE has not been performed. The Aim is to evaluate families with multiple cases of EoE by genomic and transcriptomic sequencing to identify genes predisposing to EoE. Methods: We whole exome sequenced (WES) distant relative pairs (e.g., cousins) in extended EoE pedigrees and other affected relatives to identify rare, shared, potentially pathologic variants. Whole-transcriptome sequencing by RNA-Seq was performed in nuclear families with multiple EoE cases. We compared the overlap of genes from DNA and RNA sequencing for relevance to disease manifestations. Results: WES was performed in 50 familial cases in 21 EoE extended pedigrees. We observed 219 rare, candidate predisposition variants in 210 genes with complete sharing among all affected family members. Transcriptome sequencing was performed for 43 EoE cases in 18 nuclear kindreds, including 6 relatives without EoE. We observed 10,070 total differentially expressed genes compared to controls. We identified three genes (MUC16, ADGRE1, and TENM3) with evidence of rare variant sharing and differential gene expression among all affected family members. We identified 43 other genes with partial sharing of rare variants among affected family members and with differential gene expression. Several genes identified as prominent in EoE were also differentially expressed in unaffected relatives. Conclusions: Multiple genes related to immune response, barrier dysfunction, and cell adhesion were identified in familial EoE cases and unaffected family members supporting a genetic familial predisposition and a possible multi-hit background to disease pathophysiology.
2025-01-24 | GSE250595 | GEO
Project description:Whole-exome sequencing was performed on DNA samples extracted from eight patient-derived melanoma cell lines grown in vitro in serum-free EGF/bFGF-containing medium. The aim of the experiment was to search for genetic alterations responsible for phenotypic diversity of melanoma cell lines reported at the level of cell morphology, activity of signaling pathways essential for melanoma development and progression, and response to drugs.
2018-07-12 | E-MTAB-6978 | biostudies-arrayexpress
Project description:We identified a novel germline mutation of the microphthalmia-associated transcription factor (MITF - E318K). This mutation was found to be present in numerous melanoma families, as well as the general population, where its association with melanoma has a significant effect. We determined the effect of the E318K mutation on global MITF target gene transcription. We developed a tetracycline-inducible system for expression of wild type MITF or the E318K variant in melanoma cell lines with constitutively low or undetectable levels of endogenous MITF (HT144 and C32). We examined whole-genome expression profiles in these cells following induction of either wild-type or E318K MITF for 48 hours. Analysis suggests that the MITF E318K mutant exhibits differential transcriptional activity against some, though not all, target genes. Expression profiling by array
2011-12-01 | E-GEOD-31269 | biostudies-arrayexpress
Project description:We identified a novel germline mutation of the microphthalmia-associated transcription factor (MITF - E318K). This mutation was found to be present in numerous melanoma families, as well as the general population, where its association with melanoma has a significant effect. We determined the effect of the E318K mutation on global MITF target gene transcription. We developed a tetracycline-inducible system for expression of wild type MITF or the E318K variant in melanoma cell lines with constitutively low or undetectable levels of endogenous MITF (HT144 and C32). We examined whole-genome expression profiles in these cells following induction of either wild-type or E318K MITF for 48 hours. Analysis suggests that the MITF E318K mutant exhibits differential transcriptional activity against some, though not all, target genes.
2011-12-01 | GSE31269 | GEO
Project description:Genomic And Metabolomic Profiling Of Finnish Familial Dyslipidemia Families
| PRJNA324461 | ENA