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Nature Research, Nature Communications, 1(7), 2016

DOI: 10.1038/ncomms13840

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

Journal article published in 2016 by Kevin Litchfield, D. G. de Castro, Max Levy, Darshna Dudakia, Paula Proszek, Claire Shipley, Sander Basten, Elizabeth Rapley, Dt Timothy Bishop ORCID, Alison Reid, Robert Huddart, Peter Broderick ORCID, D. Gonzalez de Castro, David Gonzalez de Castro, Simon O'Connor and other authors.
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This paper is available in a repository.

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Abstract

AbstractTesticular 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.