Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.
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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 × 10<sup>-8</sup>). 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<sup>hu255h</sup>(+/-) 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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Neoplasms, Germ Cell and Embryonal
Disease Models, Animal
Genetic Predisposition to Disease
Loss of Heterozygosity
Whole Exome Sequencing
Molecular & Population Genetics
Clinical Academic Radiotherapy (Huddart)
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Nature communications, 2016, 7 pp. 13840 - ?