Abstract 941: Exome sequencing identified POT1, a telomere shelterin gene, as a major susceptibility gene for familial cutaneous malignant melanoma
Authors: Shi Jianxin , Yang Xiaohong R. , Ballew Bari , Rotunno Melissa , Calista Donato , Fargnoli Maria C. , Ghiorzo Paola , Paillerets Brigitte Bressac-de , Nagore Eduardo ,   NCI DCEG Cancer Sequencing Working Group, Hua Xing , Hyland Paula , Yin Jinhu , Vallabhaneni Haritha , Chai Weihang , Ravichandran Sarangan , Eggermont Alexander , Lathrop Mark , Peris Ketty , Bianchi-Scarra Giovanna , Landi Giorgio , Savage Sharon , Sampson Joshua , He Ji , Yeager Meredith , Goldin Lynn , Demenais Florence , Chanock Stephen , Tucker Margaret , Goldstein Alisa , Liu Yie , Landi Maria T. 
Published: May 2015

Abstract
Approximately 10% of cutaneous malignant melanoma (CMM) cases occur in a familial setting and known high-penetrance melanoma susceptibility genes (CDKN2A, CDK4, BAP1, and TERT) account for melanoma susceptibility in a small proportion of melanoma-prone families. To identify additional high-penetrance susceptibility genes for familial CMM, we performed whole exome sequencing in 101 CMM cases/obligate carriers in 56 unrelated melanoma-prone families recruited from the Romagna area in Italy. We identified a germline founder mutation in Protection Of Telomeres 1(POT1) (g.7:124493086 C&gt;T, p.S270N) in five unrelated melanoma-prone families. The mutation was also found in a single sporadic CMM case from Romagna out of 1,824 Italian cases examined, but it was not seen in public databases, our internal exome databases of over 1000 subjects, and 878 Spanish CMM cases and 3,489 controls (2,038 Italian and 1,451Spanish) genotyped. POT1 is a component of the telomeric shelterin complex that plays a critical role in maintaining telomere integrity and regulating telomere length. The p.S270N mutation is highly conserved among vertebrates and predicted to be deleterious by most computational programs we evaluated. Carriers of the p.S270N mutation had increased length and heterogeneity as well as increased average number of fragile telomeres in peripheral blood mononuclear cell (PBMC) DNA compared to age-matched CMM cases (controls) without the mutation. Exome sequencing analysis of Italian families also identified two other rare missense substitutions in POT1 (g.7:124464052 C&gt;G [p.Q623H] and g.7:124503540 C&gt;T [p.R137H]) that were found in all cases sequenced in two families. Both missense mutations are absent from public databases and 3,489 genotyped controls, and are predicted to be deleterious by most algorithms. The carriers of these two mutations showed slightly but significantly increased telomere intensity signals and telomere fragility in PBMCs compared to age-matched controls. We further sequenced POT1 exons in 768 CMM cases and 768 controls collected from Italy and we found that CMM cases showed a significant increase in the burden of rare exonic variants compared to controls (OR=5.4, 95% CI=1.5-29.2, P=0.0021). Subsequently, we identified two novel recurrent germline missense mutations in POT1 (g.7:124499043 C&gt;T, p.D224N and g.7:124469308 C&gt;G, p.A532P) in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations and that genes involved in telomere maintenance may play important roles in melanoma development.
Citation Format: Jianxin Shi, Xiaohong R. Yang, Bari Ballew, Melissa Rotunno, Donato Calista, Maria C. Fargnoli, Paola Ghiorzo, Brigitte Bressac-de Paillerets, Eduardo Nagore, NCI DCEG Cancer Sequencing Working Group, Xing Hua, Paula Hyland, Jinhu Yin, Haritha Vallabhaneni, Weihang Chai, Sarangan Ravichandran, Alexander Eggermont, Mark Lathrop, Ketty Peris, Giovanna Bianchi-Scarra, Giorgio Landi, Sharon Savage, Joshua Sampson, Ji He, Meredith Yeager, Lynn Goldin, Florence Demenais, Stephen Chanock, Margaret Tucker, Alisa Goldstein, Yie Liu, Maria T. Landi. Exome sequencing identified POT1, a telomere shelterin gene, as a major susceptibility gene for familial cutaneous malignant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 941. doi:10.1158/1538-7445.AM2014-941