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
  • Animals
  • Cilia/genetics*
  • Cilia/physiology
  • Disease Models, Animal
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Loss of Heterozygosity
  • Male
  • Microtubule-Associated Proteins/deficiency
  • Microtubule-Associated Proteins/genetics*
  • Middle Aged
  • Mutation*
  • Neoplasms, Germ Cell and Embryonal/etiology
  • Neoplasms, Germ Cell and Embryonal/genetics*
  • Pedigree
  • Risk Factors
  • Testicular Neoplasms/etiology
  • Testicular Neoplasms/genetics*
  • Zebrafish/genetics
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
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping