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
- Pedigree
- Neoplasms, Germ Cell and Embryonal/etiology
- Neoplasms, Germ Cell and Embryonal/genetics*
- Microtubule-Associated Proteins/deficiency
- Microtubule-Associated Proteins/genetics*
- Genetic Predisposition to Disease
- Female
- Male
- Animals
- Risk Factors
- Mutation*
- Zebrafish/genetics
- Cilia/genetics*
- Cilia/physiology
- Exome Sequencing
- Humans
- Middle Aged
- Testicular Neoplasms/etiology
- Testicular Neoplasms/genetics*
- Loss of Heterozygosity
- PubMed
- 27996046 Full text @ Nat. Commun.
Citation
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. (2016) Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Nature communications. 7:13840.
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