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
  • Middle Aged
  • Exome Sequencing
  • Pedigree
  • Testicular Neoplasms/etiology
  • Testicular Neoplasms/genetics*
  • Risk Factors
  • Animals
  • Neoplasms, Germ Cell and Embryonal/etiology
  • Neoplasms, Germ Cell and Embryonal/genetics*
  • Female
  • Male
  • Loss of Heterozygosity
  • Humans
  • Microtubule-Associated Proteins/deficiency
  • Microtubule-Associated Proteins/genetics*
  • Mutation*
(all 21)
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
Figure Gallery (3 images)
Show all Figures
Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
dnaaf1hu255H/+standard conditionsAdult
dnaaf1hu255H/+standard conditionsAdult
dnaaf1hu255H/+standard conditionsAdult
1 - 3 of 3
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu255H
    		Point Mutation
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    testicular germ cell cancerdnaaf1hu255H/+standard conditionsTAS
    1 - 1 of 1
    Show
    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    dnaaf1hu255H/+
    1 - 1 of 1
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
    Your Input Welcome
    We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
    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.