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Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.


ABSTRACT: 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.

SUBMITTER: Shi J 

PROVIDER: S-EPMC4056593 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.

Shi Jianxin J   Yang Xiaohong R XR   Ballew Bari B   Rotunno Melissa M   Calista Donato D   Fargnoli Maria Concetta MC   Ghiorzo Paola P   Bressac-de Paillerets Brigitte B   Nagore Eduardo E   Avril Marie Francoise MF   Caporaso Neil E NE   McMaster Mary L ML   Cullen Michael M   Wang Zhaoming Z   Zhang Xijun X   Bruno William W   Pastorino Lorenza L   Queirolo Paola P   Banuls-Roca Jose J   Garcia-Casado Zaida Z   Vaysse Amaury A   Mohamdi Hamida H   Riazalhosseini Yasser Y   Foglio Mario M   Jouenne Fanélie F   Hua Xing X   Hyland Paula L PL   Yin Jinhu J   Vallabhaneni Haritha H   Chai Weihang W   Minghetti Paola P   Pellegrini Cristina C   Ravichandran Sarangan S   Eggermont Alexander A   Lathrop Mark M   Peris Ketty K   Scarra Giovanna Bianchi GB   Landi Giorgio G   Savage Sharon A SA   Sampson Joshua N JN   He Ji J   Yeager Meredith M   Goldin Lynn R LR   Demenais Florence F   Chanock Stephen J SJ   Tucker Margaret A MA   Goldstein Alisa M AM   Liu Yie Y   Landi Maria Teresa MT  

Nature genetics 20140330 5


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 th  ...[more]

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