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

doi:10.1038/ncomms13840

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

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	13840
Journal	Nature Communications [E]
Volume	7
DOIs	https://doi.org/10.1038/ncomms13840
Publication status	Published - 20 Dec 2016

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Litchfield, K., Levy, M., Dudakia, D., Proszek, P., Shipley, C., Basten, S., Rapley, E., Bishop, D. T., Reid, A., Huddart, R., Broderick, P., Castro, D. G. D., O'Connor, S., Giles, R. H., Houlston, R. S., & Turnbull, C. (2016). Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Nature Communications [E], 7, Article 13840. https://doi.org/10.1038/ncomms13840

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title = "Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility",

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.",

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

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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 2016, 'Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility', Nature Communications [E], vol. 7, 13840. https://doi.org/10.1038/ncomms13840

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T1 - Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

AU - Litchfield, Kevin

AU - Levy, Max

AU - Dudakia, Darshna

AU - Proszek, Paula

AU - Shipley, Claire

AU - Basten, Sander

AU - Rapley, Elizabeth

AU - Bishop, D Timothy

AU - Reid, Alison

AU - Huddart, Robert

AU - Broderick, Peter

AU - Castro, David Gonzalez de

AU - O'Connor, Simon

AU - Giles, Rachel H

AU - Houlston, Richard S

AU - Turnbull, Clare

PY - 2016/12/20

Y1 - 2016/12/20

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms13840

M3 - Article

C2 - 27996046

SN - 2041-1723

VL - 7

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 13840

ER -

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

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