Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Jianxin Shi, Xiaohong R. Yang, Bari Ballew, Melissa Rotunno, Donato Calista, Maria Concetta Fargnoli, Paola Ghiorzo, Brigitte Bressac-De Paillerets, Eduardo Nagore, Marie Francoise Avril, Neil E. Caporaso, Mary L. McMaster, Michael Cullen, Zhaoming Wang, Xijun Zhang, William Bruno, Lorenza Pastorino, Paola Queirolo, Jose Banuls-Roca, Zaida Garcia-CasadoAmaury Vaysse, Hamida Mohamdi, Yasser Riazalhosseini, Mario Foglio, Fanélie Jouenne, Xing Hua, Paula L. Hyland, Jinhu Yin, Haritha Vallabhaneni, Weihang Chai, Paola Minghetti, Cristina Pellegrini, Sarangan Ravichandran, Alexander Eggermont, Mark Lathrop, Ketty Peris, Giovanna Bianchi Scarra, 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

Research output: Contribution to journalArticlepeer-review

190 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)482-486
Number of pages5
JournalNature genetics
Issue number5
StatePublished - May 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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