Dataset Information

A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.

ABSTRACT: BACKGROUND: The MC1R gene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk. OBJECTIVE: This work aims to assess the effect of different classes of MC1R variants, notably rare variants, on melanoma risk. Methods. MC1R coding region was sequenced in 1131 melanoma patients and 869 healthy controls. MC1R variants were classified as RHC (R) and non-RHC (r). Rare variants (frequency < 1%) were subdivided into two subgroups, predicted to be damaging (D) or not (nD). RESULTS: Both R and r alleles were associated with melanoma (OR?=?2.66 [2.20-3.23] and 1.51 [1.32-1.73]) and had similar population attributable risks (15.8% and 16.6%). We also identified 69 rare variants, of which 25 were novel. D variants were strongly associated with melanoma (OR?=?2.38 [1.38-4.15]) and clustered in the same MC1R domains as R alleles (intracellular 2, transmembrane 2 and 7). CONCLUSION: This work confirms the role of R and r alleles in melanoma risk in the French population and proposes a novel class of rare D variants as important melanoma risk factors. These findings may improve the definition of high-risk subjects that could be targeted for melanoma prevention and screening.

SUBMITTER: Hu HH

PROVIDER: S-EPMC4003837 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.

Hu Hui-Han HH Benfodda Mériem M Dumaz Nicolas N Gazal Steven S Gazal Steven S Descamps Vincent V Bourillon Agnès A Basset-Seguin Nicole N Riffault Angélique A Ezzedine Khaled K Bagot Martine M Bensussan Armand A Saiag Philippe P Grandchamp Bernard B Soufir Nadem N

BioMed research international 20140410

<h4>Background</h4>The MC1R gene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk.<h4>Objective</h4>This work aims to assess the effect of different classes of MC1R variants, notably rare variants, on melanoma risk. Methods. MC1R coding region was sequenced in 1131 melanoma patients and 869 healthy controls. MC1R variants were classified as RHC (R) and non-RHC (r). Rare v ...[more]

PMID: 24982914

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Project description:BackgroundGenetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken.MethodsWe identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population.ResultsWe identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci.ConclusionsOur study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants.

Project description:BACKGROUND:Women have a better melanoma prognosis, and fairer skin/hair colour. The presence of inherited MC1R variants has been associated with a better melanoma prognosis, but its interaction with sex is unknown. OBJECTIVES:To evaluate the relationship between germline MC1R status and survival, and determine any association with sex. METHODS:This was a cohort study including 1341 patients with melanoma from the Melanoma Unit of the Hospital Clinic of Barcelona, between January 1996 and April 2018. We examined known sex-related prognosis factors as they relate to features of melanoma and evaluated the sex-specific role of MC1R in overall and melanoma-specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox logistic regression. RESULTS:Men showed lower overall survival than women (P < 0·001) and the presence of inherited MC1R variants was not associated with better survival in our cohort. However, in women the presence of MC1R variants was associated with better overall survival in the multivariate analysis [HR 0·57, 95% confidence interval (CI) 0·38-0·85; P = 0·006] but not in men [HR 1·26, 95% CI 0·89-1·79; P = 0·185 (P-value for interaction 0·004)]. Analysis performed for melanoma-specific survival showed the same level of significance. CONCLUSIONS:Inherited MC1R variants are associated with improved overall survival in women with melanoma but not in men. Intrinsic sex-dependent features can modify the role of specific genes in melanoma prognosis. We believe that survival studies of patients with melanoma should include analysis by sex and MC1R genotype. What's already known about this topic? Inherited MC1R variants have been associated with a better melanoma prognosis, but their interaction with sex is unknown. What does this study add? MC1R variants are related to better overall survival and melanoma-specific survival in women but not in men. What is the translational message? These differences between the sexes could imply future changes in melanoma follow-up and treatment strategies. This provides a basis for understanding the interaction between sex-related genes and germline variants in cancer.

Dataset Information

A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.

Publications

A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.

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