Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility.
Loading...
Embargo End Date
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
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)
Molecular & Population Genetics
Clinical Academic Radiotherapy (Huddart)