Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
Jianxin Shi,Xiaohong R. Yang,Bari J. Ballew,Melissa Rotunno,Donato Calista,Maria Concetta Fargnoli,Paola Ghiorzo,Brigitte Bressac-de Paillerets,Eduardo Nagore,Marie-Françoise Avril,Neil E. Caporaso,Mary L. McMaster,Michael Cullen,Michael Cullen,Zhaoming Wang,Zhaoming Wang,Xijun Zhang,Xijun Zhang,William Bruno,Lorenza Pastorino,Paola Queirolo,Jose Banuls-Roca,Zaida García-Casado,Amaury Vaysse,Amaury Vaysse,Hamida Mohamdi,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 M.M. Eggermont,Alexander M.M. Eggermont,Mark Lathrop,Mark Lathrop,Ketty Peris,Giovanna Bianchi Scarrà,Giorgio Landi,Sharon A. Savage,Joshua N. Sampson,Ji He,Ji He,Meredith Yeager,Meredith Yeager,Lynn R. Goldin,Florence Demenais,Florence Demenais,Stephen J. Chanock,Margaret A. Tucker,Alisa M. Goldstein,Yie Liu,Maria Teresa Landi +58 more
TLDR
The findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations, and that this variant perturbs telomere maintenance.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.read more
Citations
More filters
Journal ArticleDOI
From melanocytes to melanomas
A. Hunter Shain,Boris C. Bastian +1 more
TL;DR: This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.
Journal ArticleDOI
Telomeres in cancer: tumour suppression and genome instability
John Maciejowski,Titia de Lange +1 more
TL;DR: Current data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomeres crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
Journal ArticleDOI
POT1 loss-of-function variants predispose to familial melanoma
Carla Daniela Robles-Espinoza,Mark Harland,Andrew J. Ramsay,Lauren G. Aoude,Víctor Quesada,Zhihao Ding,Karen A. Pooley,Antonia L. Pritchard,Jessamy Tiffen,Mia Petljak,Jane M. Palmer,Judith Symmons,Peter Johansson,Mitchell S. Stark,Michael Gartside,Helen Snowden,Grant W. Montgomery,Nicholas G. Martin,Jimmy Z. Liu,Jiyeon Choi,Matthew M. Makowski,Kevin M. Brown,Alison M. Dunning,Thomas M. Keane,Carlos López-Otín,Nelleke A. Gruis,Nicholas K. Hayward,D. Timothy Bishop,Julia Newton-Bishop,David J. Adams +29 more
TL;DR: It is shown that POT1 variants predispose to melanoma formation via a direct effect on telomeres, disrupting protein-telomere binding and leading to increased telomere length.
Journal ArticleDOI
Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma
Matthew Law,D. Timothy Bishop,Jeffrey E. Lee,Myriam Brossard,Nicholas G. Martin,Eric K. Moses,Fengju Song,Jennifer H. Barrett,Rajesh Kumar,Douglas F. Easton,Paul D.P. Pharoah,Anthony J. Swerdlow,Katerina P. Kypreou,John C. Taylor,Mark Harland,Juliette Randerson-Moor,Lars A. Akslen,Per Arne Andresen,Marie-Françoise Avril,Esther Azizi,Giovanna Bianchi Scarrà,Kevin M. Brown,Tadeusz Dębniak,David L. Duffy,David E. Elder,Shenying Fang,Eitan Friedman,Pilar Galan,Paola Ghiorzo,Elizabeth M. Gillanders,Alisa M. Goldstein,Nelleke A. Gruis,Johan Hansson,Per Helsing,Marko Hočevar,Veronica Höiom,Christian Ingvar,Peter A. Kanetsky,Wei V. Chen,Maria Teresa Landi,Julie Lang,G. Mark Lathrop,Jan Lubinski,Rona M. MacKie,Graham J. Mann,Anders Molven,Grant W. Montgomery,Srdjan Novaković,Håkan Olsson,Susana Puig,Joan Anton Puig-Butille,Abrar A. Qureshi,Graham L. Radford-Smith,Nienke van der Stoep,Remco van Doorn,David C. Whiteman,Jamie E Craig,Dirk Schadendorf,Lisa A. Simms,Kathryn P. Burdon,Dale R. Nyholt,Karen A. Pooley,Nick Orr,Alexander J. Stratigos,Anne E. Cust,Sarah V. Ward,Nicholas K. Hayward,Jiali Han,Hans Joachim Schulze,Alison M. Dunning,Julia A. Newton Bishop,Florence Demenais,Christopher I. Amos,Stuart MacGregor,Mark M. Iles +74 more
TL;DR: An international 2-stage meta-analysis of CMM genome-wide association studies (GWAS) combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls, finding five loci not previously associated with CMM risk reached genome- wide significance.
Journal ArticleDOI
Childhood cancer predisposition syndromes : A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology
Tim Ripperger,Stefan S. Bielack,Arndt Borkhardt,Ines B. Brecht,Ines B. Brecht,Birgit Burkhardt,Gabriele Calaminus,Klaus-Michael Debatin,Hedwig E. Deubzer,Uta Dirksen,Cornelia Eckert,Angelika Eggert,Miriam Erlacher,Gudrun Fleischhack,Michael C. Frühwald,Astrid Gnekow,Gudrun Goehring,Norbert Graf,Helmut Hanenberg,Julia Hauer,Barbara Hero,Simone Hettmer,Katja von Hoff,Martin A. Horstmann,Juliane Hoyer,Thomas Illig,Peter Kaatsch,Roland Kappler,Kornelius Kerl,Thomas Klingebiel,Udo Kontny,Uwe Kordes,Dieter Körholz,Ewa Koscielniak,Christof M. Kramm,Michaela Kuhlen,Andreas E. Kulozik,Britta Lamottke,Ivo Leuschner,Dietmar R. Lohmann,Andrea Meinhardt,Markus Metzler,Lüder Hinrich Meyer,Olga Moser,Michaela Nathrath,Charlotte M. Niemeyer,Rainer Nustede,Kristian W. Pajtler,Kristian W. Pajtler,Claudia Paret,Mareike Rasche,Dirk Reinhardt,Olaf Rieß,Alexandra Russo,Stefan Rutkowski,Brigitte Schlegelberger,Dominik T. Schneider,Reinhard Schneppenheim,Martin Schrappe,Christopher Schroeder,Dietrich von Schweinitz,Thorsten Simon,Monika Sparber-Sauer,Claudia Spix,Martin Stanulla,Doris Steinemann,Brigitte Strahm,Petra Temming,Kathrin Thomay,André O. von Bueren,Peter Vorwerk,Olaf Witt,Marcin W. Wlodarski,Willy Wössmann,Martin Zenker,Stefanie Zimmermann,Stefan M. Pfister,Stefan M. Pfister,Christian P. Kratz +78 more
TL;DR: This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer genetic predisposition syndrome should be suspected.
References
More filters
Journal ArticleDOI
PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
Shaun Purcell,Shaun Purcell,Benjamin M. Neale,Benjamin M. Neale,Kathe Todd-Brown,Lori Thomas,Manuel A. R. Ferreira,David Bender,David Bender,Julian Maller,Julian Maller,Pamela Sklar,Pamela Sklar,Paul I.W. de Bakker,Paul I.W. de Bakker,Mark J. Daly,Mark J. Daly,Pak C. Sham +17 more
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Journal ArticleDOI
A framework for variation discovery and genotyping using next-generation DNA sequencing data
Mark A. DePristo,Eric Banks,Ryan Poplin,Kiran V. Garimella,Jared Maguire,Christopher Hartl,Anthony A. Philippakis,Anthony A. Philippakis,Anthony A. Philippakis,Guillermo del Angel,Manuel A. Rivas,Manuel A. Rivas,Matt Hanna,Aaron McKenna,Timothy Fennell,Andrew Kernytsky,Andrey Sivachenko,Kristian Cibulskis,Stacey Gabriel,David Altshuler,David Altshuler,Mark J. Daly,Mark J. Daly +22 more
TL;DR: A unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs is presented.
Journal ArticleDOI
Jalview Version 2--a multiple sequence alignment editor and analysis workbench.
TL;DR: Jalview 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server.
Journal ArticleDOI
T-Coffee: A novel method for fast and accurate multiple sequence alignment.
TL;DR: A new method for multiple sequence alignment that provides a dramatic improvement in accuracy with a modest sacrifice in speed as compared to the most commonly used alternatives but avoids the most serious pitfalls caused by the greedy nature of this algorithm.
Journal ArticleDOI
dbSNP: the NCBI database of genetic variation
Stephen T. Sherry,Minghong Ward,Michael Kholodov,Jonathan Baker,Lon Phan,Elizabeth M. Smigielski,Karl Sirotkin +6 more
TL;DR: The dbSNP database is a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, and is integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data.