PUBLICATION
Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility
- Authors
- Litchfield, K., Levy, M., Dudakia, D., Proszek, P., Shipley, C., Basten, S., Rapley, E., Bishop, D.T., Reid, A., Huddart, R., Broderick, P., Castro, D.G., O'Connor, S., Giles, R.H., Houlston, R.S., Turnbull, C.
- ID
- ZDB-PUB-161221-4
- Date
- 2016
- Source
- Nature communications 7: 13840 (Journal)
- Registered Authors
- Keywords
- Cancer genomics, Development, Germ cell tumours
- MeSH Terms
-
- Disease Models, Animal
- Zebrafish/genetics
- Genetic Predisposition to Disease
- Cilia/genetics*
- Cilia/physiology
- PubMed
- 27996046 Full text @ Nat. Commun.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping