Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer Beatriz Paumard-Hern andez 1 , Oriol Calvete 1,2 , Lucia Inglada P erez 2,3 ,H ector Tejero 4 ,F atima Al-Shahrour 4 , Guillermo Pita 5 , Alicia Barroso 1 , Juan Carlos Trivi~ no 6 , Miguel Urioste 2,7 , Claudia Valverde 8,9 , Enrique Gonz alez Billalabeitia 9,10 , Vanesa Quiroga 9,11 , Juan Francisco Rodr  ıguez Moreno 9,12 , Antonio Fern andez Aramburo 9,13 , Cristina L opez 9,14 , Pablo Maroto 9,15 , Javier Sastre 9,16 , Mar  ıa Jos e Juan Fita 9,17 , Ignacio Duran 9,18 , Isabel Lorenzo-Lorenzo 19 , Patricia Iranzo 9,20 , Xavier Garc  ıa del Muro 9,21 , Silverio Ros 22 , Francisco Zambrana 9,23 , Ana Mar  ıa Autran 9,24 and Javier Ben  ıtez 1,2,5 1 Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 2 Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain 3 Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain 4 Bioinformatics Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain 5 Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 6 Bioinformatic Unit, Sistemas Gen omicos, Valencia Spain, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 7 Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain 8 Department of Medical Oncology, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain 9 Spanish Germ Cell Group (SGCCG) 10 Medical Oncology-Haematology Department, Hospital Universitario Morales Meseguer, Murcia, Spain 11 Medical Oncology Department, Hospital Universitari Germans Trias i Pujol, Institut Catal a d’Oncologia-Badalona, Barcelona, Spain 12 Division of Medical Oncology, Clara Campal Comprehensive Cancer Center, Madrid, Spain 13 Department of Oncology, Complejo Hospitalario Universitario Albacete, Albacete, Spain 14 Medical Oncology Department, Instituto de Investigaci on Sanitaria Gregorio Mara~ n on, Madrid, Spain 15 Medical Oncology and Biochemistry Departments, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 16 Department of Medical Oncology, Hospital Cl  ınico San Carlos, Instituto de Investigaci on Sanitaria del Hospital Cl  ınico San Carlos (IdISSC), Madrid, Spain 17 Medical Oncology, Fundaci on Instituto Valenciano de Oncolog  ıa, Valencia, Spain 18 Department of Medical Oncology, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Roc  ıo/CSIC/Universidad de Sevilla, Sevilla, Spain 19 Medical Oncology Service, Complejo Universitario Hospitalario de Vigo, Spain 20 Department of Medical Oncology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain 21 Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Catal a d’Oncologia Hospitalet, IDIBELL, Barcelona, Spain 22 Department of Clinical Oncology, Hospital Universitario Virgen Arrixaca, Murcia, Spain 23 Medical Oncology Department, Hospital Universitario Infanta Sof  ıa, San Sebasti an De Los Reyes, Spain 24 Medical Urology department, Fundaci on Jim enez D  ıaz, Madrid, Spain 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 Key words: testicular germ cell tumor, susceptibility risk variants, whole exome sequencing Abbreviations: CADD: combined annotation dependent depletion; CIBERER: Centre for Biomedical Research on Rare Diseases; CNIO: Spanish National Cancer Research Centre; DNAH7: dynein axonemal heavy chain 7; ExAC: Exome Aggregation Consortium; EXO5: exonuclease 5; FB-SKAT: family-based sequence Kernel association test; MAF: minor allele frequency; PCR: polymerase chain reaction; PLEC: plectin; SKAT: sequence Kernel association test; TGCT: testicular germ cell tumors; WES: whole exome sequencing Additional Supporting Information may be found in the online version of this article. Grant sponsor: Long-Term Care)?>Spanish Ministry of Health; Grant numbers: PI16/00440, PI16/00440; Grant sponsor: BRIDGES Project (H2020) (to J.B.); Grant sponsor: “La Caixa”—Severo Ochoa International PhD Program at the CNIO (to B.P.); Grant sponsor: BRIDGES Project; Grant number: H2020; Grant sponsor: Obra social La Caixa; Grant number: “La Caixa”- Severo Ochoa International PhD; Grant sponsor: Spanish Ministry of Health Spanish Ministry of Health; Grant number: PI12/00070 DOI: 10.1002/ijc.31604 History: Received 26 Jan 2018; Accepted 20 Apr 2018; Online 15 May 2018 Correspondence to: Javier Ben  ıtez, Spanish National Cancer Research Center (CNIO), C/Melchor Fern andez Almagro, 3. E-28029 Madrid, Spain, Tel.: 134-917328000, ext. 3300, Fax: 134-912246911, E-mail: jbenitez@cnio.es Cancer Genetics and Epigenetics Int. J. Cancer: 00, 00–00 (2018) V C 2018 UICC International Journal of Cancer IJC International Journal of Cancer IJC Int. J. Cancer: 143, 1954–1962 (2018) © 2018 UICC Cancer Genetics and Epigenetics