1. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma
- Author
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Ketty Peris, Zhaoming Wang, Donato Calista, Ji He, Lynn R. Goldin, Marie-Françoise Avril, Margaret A. Tucker, Lorenza Pastorino, Fanélie Jouenne, William Bruno, Melissa Rotunno, Mario Foglio, Florence Demenais, Giovanna Bianchi Scarrà, Weihang Chai, Bari J. Ballew, Paola Minghetti, Amaury Vaysse, Sarangan Ravichandran, Maria Concetta Fargnoli, Sharon A. Savage, Paola Queirolo, Maria Teresa Landi, Paula L. Hyland, Jianxin Shi, Alisa M. Goldstein, Joshua N. Sampson, Alexander M.M. Eggermont, Haritha Vallabhaneni, Yie Liu, Hamida Mohamdi, Paola Ghiorzo, Michael Cullen, Jinhu Yin, Mark Lathrop, Cristina Pellegrini, Eduardo Nagore, Neil E. Caporaso, Mary L. McMaster, Zaida García-Casado, Yasser Riazalhosseini, Xing Hua, Stephen J. Chanock, Jose Banuls-Roca, Xijun Zhang, Brigitte Bressac-de Paillerets, Xiaohong R. Yang, Giorgio Landi, and Meredith Yeager
- Subjects
Models, Molecular ,medicine.medical_specialty ,Skin Neoplasms ,Population ,Molecular Sequence Data ,Telomere-Binding Proteins ,Mutation, Missense ,Biology ,medicine.disease_cause ,Shelterin Complex ,Article ,CDKN2A ,Genetics ,medicine ,melanoma ,Missense mutation ,Humans ,Exome ,Genetic Predisposition to Disease ,Amino Acid Sequence ,education ,In Situ Hybridization, Fluorescence ,Chromosome 7 (human) ,education.field_of_study ,Mutation ,Neoplasms, Connective Tissue ,Base Sequence ,Computational Biology ,Telomere Homeostasis ,Sequence Analysis, DNA ,Shelterin ,United States ,3. Good health ,Telomere ,Pedigree ,Italy ,Medical genetics ,France ,Settore MED/35 - MALATTIE CUTANEE E VENEREE ,Sequence Alignment - 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.
- Published
- 2014