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Whole exome sequencing identifies PLEC , EXO5 and DNAH7 as novel susceptibility genes in testicular cancer
Author(s) -
PaumardHernández Beatriz,
Calvete Oriol,
Inglada Pérez Lucia,
Tejero Héctor,
AlShahrour Fátima,
Pita Guillermo,
Barroso Alicia,
Carlos Triviño Juan,
Urioste Miguel,
Valverde Claudia,
González Billalabeitia Enrique,
Quiroga Vanesa,
Francisco Rodríguez Moreno Juan,
Fernández Aramburo Antonio,
López Cristina,
Maroto Pablo,
Sastre Javier,
José Juan Fita María,
Duran Ignacio,
LorenzoLorenzo Isabel,
Iranzo Patricia,
García del Muro Xavier,
Ros Silverio,
Zambrana Francisco,
María Autran Ana,
Benítez Javier
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31604
Subject(s) - exome sequencing , exome , candidate gene , biology , cancer , genetics , genome wide association study , case control study , disease , genetic association , odds ratio , gene , genotype , oncology , medicine , single nucleotide polymorphism , mutation
Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case–control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann–Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [ PLEC (OR = 6.28, p = 6.42 × 10 −23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10 −09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.