Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Renea A. Taylor; Michael Fraser; Julie Livingstone; Shadrielle Melijah G. Espiritu; Heather Thorne; Vincent Huang; Winnie Lo; Yu Jia Shiah; Takafumi N. Yamaguchi; Ania Sliwinski; Sheri Horsburgh; Alice Meng; Lawrence E. Heisler; Nancy Yu; Fouad Yousif; Melissa Papargiris; Mitchell G. Lawrence; Lee Timms; Declan G. Murphy; Mark Frydenberg; Julia F. Hopkins; Damien Bolton; David Clouston; John D. McPherson; Theodorus Van Der Kwast; Paul C. Boutros; Gail P. Risbridger; Robert G. Bristow

doi:10.1038/ncomms13671

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Renea A. Taylor, Michael Fraser, Julie Livingstone, Shadrielle Melijah G. Espiritu, Heather Thorne, Vincent Huang, Winnie Lo, Yu Jia Shiah, Takafumi N. Yamaguchi, Ania Sliwinski, Sheri Horsburgh, Alice Meng, Lawrence E. Heisler, Nancy Yu, Fouad Yousif, Melissa Papargiris, Mitchell G. Lawrence, Lee Timms, Declan G. Murphy, Mark FrydenbergJulia F. Hopkins, Damien Bolton, David Clouston, John D. McPherson, Theodorus Van Der Kwast, Paul C. Boutros, Gail P. Risbridger, Robert G. Bristow

Division of Cancer Sciences (L5)

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

Abstract

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

Original language	English
Article number	13671
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms13671
Publication status	Published - 9 Jan 2017

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Manchester Cancer Research Centre

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10.1038/ncomms13671

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Taylor, R. A., Fraser, M., Livingstone, J., Espiritu, S. M. G., Thorne, H., Huang, V., Lo, W., Shiah, Y. J., Yamaguchi, T. N., Sliwinski, A., Horsburgh, S., Meng, A., Heisler, L. E., Yu, N., Yousif, F., Papargiris, M., Lawrence, M. G., Timms, L., Murphy, D. G., ... Bristow, R. G. (2017). Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nature Communications, 8, Article 13671. https://doi.org/10.1038/ncomms13671

@article{d6ebc15b38d24e25a49e1a6abd2f433b,

title = "Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories",

abstract = "Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.",

author = "Taylor, {Renea A.} and Michael Fraser and Julie Livingstone and Espiritu, {Shadrielle Melijah G.} and Heather Thorne and Vincent Huang and Winnie Lo and Shiah, {Yu Jia} and Yamaguchi, {Takafumi N.} and Ania Sliwinski and Sheri Horsburgh and Alice Meng and Heisler, {Lawrence E.} and Nancy Yu and Fouad Yousif and Melissa Papargiris and Lawrence, {Mitchell G.} and Lee Timms and Murphy, {Declan G.} and Mark Frydenberg and Hopkins, {Julia F.} and Damien Bolton and David Clouston and McPherson, {John D.} and {Van Der Kwast}, Theodorus and Boutros, {Paul C.} and Risbridger, {Gail P.} and Bristow, {Robert G.}",

year = "2017",

month = jan,

day = "9",

doi = "10.1038/ncomms13671",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

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Taylor, RA, Fraser, M, Livingstone, J, Espiritu, SMG, Thorne, H, Huang, V, Lo, W, Shiah, YJ, Yamaguchi, TN, Sliwinski, A, Horsburgh, S, Meng, A, Heisler, LE, Yu, N, Yousif, F, Papargiris, M, Lawrence, MG, Timms, L, Murphy, DG, Frydenberg, M, Hopkins, JF, Bolton, D, Clouston, D, McPherson, JD, Van Der Kwast, T, Boutros, PC, Risbridger, GP & Bristow, RG 2017, 'Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories', Nature Communications, vol. 8, 13671. https://doi.org/10.1038/ncomms13671

TY - JOUR

T1 - Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

AU - Taylor, Renea A.

AU - Fraser, Michael

AU - Livingstone, Julie

AU - Espiritu, Shadrielle Melijah G.

AU - Thorne, Heather

AU - Huang, Vincent

AU - Lo, Winnie

AU - Shiah, Yu Jia

AU - Yamaguchi, Takafumi N.

AU - Sliwinski, Ania

AU - Horsburgh, Sheri

AU - Meng, Alice

AU - Heisler, Lawrence E.

AU - Yu, Nancy

AU - Yousif, Fouad

AU - Papargiris, Melissa

AU - Lawrence, Mitchell G.

AU - Timms, Lee

AU - Murphy, Declan G.

AU - Frydenberg, Mark

AU - Hopkins, Julia F.

AU - Bolton, Damien

AU - Clouston, David

AU - McPherson, John D.

AU - Van Der Kwast, Theodorus

AU - Boutros, Paul C.

AU - Risbridger, Gail P.

AU - Bristow, Robert G.

PY - 2017/1/9

Y1 - 2017/1/9

N2 - Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

AB - Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

UR - http://www.scopus.com/inward/record.url?scp=85009062686&partnerID=8YFLogxK

U2 - 10.1038/ncomms13671

DO - 10.1038/ncomms13671

M3 - Article

AN - SCOPUS:85009062686

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 13671

ER -

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Abstract

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