Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

Nat Commun. 2016 Dec 20:7:13840. doi: 10.1038/ncomms13840.


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.

Publication types

  • Research Support, Non-U.S. Gov't

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


  • DNAAF1 protein, human
  • Microtubule-Associated Proteins

Supplementary concepts

  • Testicular Germ Cell Tumor