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

Kevin Litchfield, Max Levy, Darshna Dudakia, Paula Proszek, Claire Shipley, Sander Basten, Elizabeth Rapley, D Timothy Bishop, Alison Reid, Robert Huddart, Peter Broderick, David Gonzalez de Castro, Simon O'Connor, Rachel H. Giles, Richard S Houlston, Clare Turnbull

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25 Citations (Scopus)
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Abstract

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 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.

Original languageEnglish
Article number13840
Number of pages8
JournalNature Communications
Volume7
Early online date20 Dec 2016
DOIs
Publication statusPublished - 2016

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