Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.
Date
2016-12-20Author
Litchfield, K
Levy, M
Dudakia, D
Proszek, P
Shipley, C
Basten, S
Rapley, E
Bishop, DT
Reid, A
Huddart, R
Broderick, P
Castro, DGD
O'Connor, S
Giles, RH
Houlston, RS
Turnbull, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cilia
Animals
Zebrafish
Humans
Neoplasms, Germ Cell and Embryonal
Testicular Neoplasms
Disease Models, Animal
Genetic Predisposition to Disease
Microtubule-Associated Proteins
Risk Factors
Pedigree
Mutation
Loss of Heterozygosity
Middle Aged
Female
Male
Whole Exome Sequencing
Research team
Cancer Genomics
Molecular & Population Genetics
Clinical Academic Radiotherapy (Huddart)
Language
eng
Date accepted
2016-11-04
License start date
2016-12-20
Citation
Nature communications, 2016, 7 pp. 13840 - ?
Publisher
NATURE PUBLISHING GROUP