Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

• DOI: 10.1038/ng.2941
• Publication Date: 2014-04-01T04:08:27Z
• Authors: Jianxin Shi; ; ; Xiaohong R Yang; Bari Ballew; Melissa Rotunno; Donato Calista; Maria Concetta Fa...; Paola Ghiorzo; Brigitte Bressac-...; Eduardo Nagore; Marie Francoise A...; Neil E Caporaso; Mary L McMaster; Michael Cullen; Zhaoming Wang; Xijun Zhang; William Bruno; Lorenza Pastorino; Paola Queirolo; Jose Banuls-Roca; Zaida Garcia-Casado; Amaury Vaysse; Hamida Mohamdi; Yasser Riazalhoss...; Mario Foglio; Fanélie Jouenne; Xing Hua; Paula L Hyland; Jinhu Yin; Haritha Vallabhaneni; Weihang Chai; Paola Minghetti; Cristina Pellegrini; Sarangan Ravichan...; Alexander Eggermont; Mark Lathrop; Ketty Peris; Giovanna Bianchi ...; Giorgio Landi; Sharon A Savage; Joshua N Sampson; Ji He; Meredith Yeager; Lynn R Goldin; Florence Demenais; Stephen J Chanock; Margaret A Tucker; Alisa M Goldstein; Yie Liu; Maria Teresa Landi
• Keywords: Models, Molecular; Skin Neoplasms; Molecular Sequence Data; Mutation, Missense; Telomere-Binding Proteins - chemistry; 610; Fluorescence; Article; Shelterin Complex; 03 medical and health sciences; Telomere-Binding Proteins - genetics; Models; Neoplasms; 616; melanoma; Humans; Exome; Genetic Predisposition to Disease; Amino Acid Sequence; Missense - genetics; Melanoma; In Situ Hybridization; In Situ Hybridization, Fluorescence; Melanoma - genetics; Neoplasms, Connective Tissue; 0303 health sciences; Exome - genetics; Base Sequence; Telomere Homeostasis - genetics; Molecular; Computational Biology; Telomere Homeostasis; DNA; Sequence Analysis, DNA; United States; Pedigree; 3. Good health; Connective Tissue - genetics; Italy; Mutation; Genetic Predisposition to Disease - genetics; France; Sequence Analysis; Sequence Alignment

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.