Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms13840
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Funding
- National Health Service
- Movember foundation
- Institute of Cancer Research
- Cancer Research UK [C1298/A8362]
- Dutch Kidney Foundation KOUNCIL program [CP11.18]
- Cancer Research UK [19167, 10589] Funding Source: researchfish
- Medical Research Council [MR/N01104X/1, G1001799, MR/L01629X/1] Funding Source: researchfish
- MRC [MR/L01629X/1, MR/N01104X/1, G1001799] Funding Source: UKRI
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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 x 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 dnaaf1(hu255h)(+/-) 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.
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