Journal Article

Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Yin, Jinhu, Shi, Jianxin, Minghetti, Paola, Mohamdi, Hamida, Ravichandran, Sarangan, Calista, Donato, Scarra, Giovanna Bianchi, Goldin, Lynn R, Tucker, Margaret A, Foglio, Mario, Vaysse, Amaury, Avril, Marie Francoise, Demenais, Florence, Liu, Yie, Bruno, William, Goldstein, Alisa M, Savage, Sharon A, Pellegrini, Cristina, Peris, Ketty, Yeager, Meredith, Pastorino, Lorenza, Hua, Xing, Lathrop, Mark, Ballew, Bari, Wang, Zhaoming, Vallabhaneni, Haritha, Hyland, Paula L, Rotunno, Melissa, Fargnoli, Maria Concetta, Chai, Weihang, Queirolo, Paola, Nagore, Eduardo, Landi, Giorgio, Jouenne, Fanélie, Eggermont, Alexander, Ghiorzo, Paola, Bressac-de Paillerets, Brigitte, Landi, Maria Teresa, Garcia-Casado, Zaida, Caporaso, Neil E, McMaster, Mary L, Sampson, Joshua N, He, Ji, Chanock, Stephen J, Zhang, Xijun, Yang, Xiaohong R, Cullen, Michael, Banuls-Roca, Jose, Riazalhosseini, Yasser

2014

Overview

Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility. Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 631/208/2489 / 692/699/67/1813/1634 / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Base Sequence / Binding sites / Biomedicine / Cancer Research / Computational Biology / Deoxyribonucleic acid / DNA / Epidemiology / Exome - genetics / France / Gene Function / Genealogy / Genes / Genetic aspects / Genetic factors / Genetic Predisposition to Disease - genetics / Genetic research / Genetic susceptibility / Genomics / Health aspects / Human Genetics / Humans / In Situ Hybridization, Fluorescence / Italy / letter / Melanoma / Melanoma - genetics / Melanoma, Cutaneous Malignant / Models, Molecular / Molecular Sequence Data / Mutation / Mutation, Missense - genetics / Neoplasms, Connective Tissue - genetics / Pedigree / Risk factors / Sequence Alignment / Sequence Analysis, DNA / Shelterin Complex / Skin cancer / Skin Neoplasms / Telomerase / Telomere Homeostasis - genetics / Telomere-Binding Proteins - chemistry / Telomere-Binding Proteins - genetics / Telomeres / United States