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

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Authors

Litchfield, K
Levy, M
Dudakia, D
Proszek, P
Shipley, C
Basten, S
Rapley, E
Bishop, DT
Reid, A
Huddart, R
Broderick, P
Castro, DGD
O'Connor, S
Giles, RH
Houlston, RS
Turnbull, C

Document Type

Journal Article

Date

2016-12-20

Date Accepted

2016-11-04

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 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.

Citation

Nature communications, 2016, 7 pp. 13840 - ?

Source Title

Publisher

NATURE PUBLISHING GROUP

ISSN

2041-1723

eISSN

2041-1723

Research Team

Cancer Genomics
Molecular & Population Genetics
Clinical Academic Radiotherapy (Huddart)

Notes