Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.
Kevin LitchfieldMax LevyDarshna DudakiaPaula ProszekClaire ShipleySander BastenElizabeth RapleyD Timothy Timothy BishopAlison ReidRobert HuddartPeter BroderickDavid Gonzalez de CastroSimon O'ConnorRachel H GilesRichard S HoulstonClare TurnbullPublished in: Nature communications (2016)
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.
Keyphrases
- germ cell
- papillary thyroid
- genome wide
- squamous cell
- bioinformatics analysis
- genome wide identification
- lymph node metastasis
- childhood cancer
- gene expression
- dna methylation
- middle aged
- young adults
- autism spectrum disorder
- transcription factor
- machine learning
- electronic health record
- intellectual disability
- early onset
- big data
- binding protein