title: Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.
abstract: Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 × 10-8). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu255h(+/-) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Litchfield
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Levy
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Darshna
authors.initials: D
authors.lastname: Dudakia
authors.affiliation: Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Proszek
authors.affiliation: Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Shipley
authors.affiliation: Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Uppsalalaan 6, Utrecht 3584CT, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Basten
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rapley
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds LS9 7TF, UK.
authors.forename: D Timothy
authors.identifier: 0000-0002-8752-8785
authors.initials: DT
authors.lastname: Bishop
authors.forename: Alison
authors.initials: A
authors.lastname: Reid
authors.forename: Robert
authors.initials: R
authors.lastname: Huddart
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Peter
authors.identifier: 0000-0002-8348-5829
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.|Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK.
authors.forename: David Gonzalez de
authors.initials: DG
authors.lastname: Castro
authors.affiliation: Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: O'Connor
authors.affiliation: Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Uppsalalaan 6, Utrecht 3584CT, The Netherlands.
authors.forename: Rachel H
authors.identifier: 0000-0001-9133-2008
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.|Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.|William Harvey Research Institute, Queen Mary University, London EC1M 6BQ, UK.|Department of Clinical Genetics, Guy's and St Thomas' NHS Trust, London SE1 9RS, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009373:Neoplasms, Germ Cell and Embryonal / Q000209:etiology / Q000235:genetics*; D010375:Pedigree; D012307:Risk Factors; D013736:Testicular Neoplasms / Q000209:etiology / Q000235:genetics*; D000073359:Exome Sequencing; D015027:Zebrafish / Q000235:genetics
chemical_list: C546358:DNAAF1 protein, human; D008869:Microtubule-Associated Proteins