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Int J Cancer. 2018 Oct 15;143(8):1954-1962. doi: 10.1002/ijc.31604. Epub 2018 Aug 9.

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

Author information

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 Genómicos, 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 Català 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 Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
15
Medical Oncology and Biochemistry Departments, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
16
Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
17
Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
18
Department of Medical Oncology, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/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 Català d'Oncologia Hospitalet, IDIBELL, Barcelona, Spain.
22
Department of Clinical Oncology, Hospital Universitario Virgen Arrixaca, Murcia, Spain.
23
Medical Oncology Department, Hospital Universitario Infanta Sofía, San Sebastián De Los Reyes, Spain.
24
Medical Urology department, Fundación Jiménez Díaz, Madrid, Spain.

Abstract

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.

KEYWORDS:

susceptibility risk variants; testicular germ cell tumor; whole exome sequencing

PMID:
29761480
DOI:
10.1002/ijc.31604
[Indexed for MEDLINE]

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