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 & 8 others Julia F. Hopkins, Damien Bolton, David Clouston, John D. McPherson, Theodorus Van Der Kwast, Paul C. Boutros, Gail P. Risbridger, Robert G. Bristow

Research output: Contribution to journalArticleResearchpeer-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 languageEnglish
Article number13671
Number of pages10
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 9 Jan 2017

Keywords

  • cancer genetics
  • cancer genomics
  • prostate cancer

Cite this

Taylor, R. A., Fraser, M., Livingstone, J., Espiritu, S. M. G., Thorne, H., Huang, V., ... Bristow, R. G. (2017). Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nature Communications, 8, [13671]. https://doi.org/10.1038/ncomms13671
Taylor, Renea A. ; Fraser, Michael ; Livingstone, Julie ; Espiritu, Shadrielle Melijah G. ; Thorne, Heather ; Huang, Vincent ; Lo, Winnie ; Shiah, Yu-Jia ; Yamaguchi, Takafumi N. ; Sliwinski, Ania ; Horsburgh, Sheri ; Meng, Alice ; Heisler, Lawrence E. ; Yu, Nancy ; Yousif, Fouad ; Papargiris, Melissa ; Lawrence, Mitchell G. ; Timms, Lee ; Murphy, Declan G. ; Frydenberg, Mark ; Hopkins, Julia F. ; Bolton, Damien ; Clouston, David ; McPherson, John D. ; Van Der Kwast, Theodorus ; Boutros, Paul C. ; Risbridger, Gail P. ; Bristow, Robert G. / Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. In: Nature Communications. 2017 ; Vol. 8.
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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.",
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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 Yu-Jia Shiah 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.}",
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Taylor, RA, Fraser, M, Livingstone, J, Espiritu, SMG, Thorne, H, Huang, V, Lo, W, Shiah, Y-J, 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

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. / Taylor, Renea A.; Fraser, Michael; Livingstone, Julie; Espiritu, Shadrielle Melijah G.; Thorne, Heather; Huang, Vincent; Lo, Winnie; Shiah, Yu-Jia; Yamaguchi, Takafumi N.; Sliwinski, Ania; Horsburgh, Sheri; Meng, Alice; Heisler, Lawrence E.; Yu, Nancy; Yousif, Fouad; Papargiris, Melissa; Lawrence, Mitchell G.; Timms, Lee; Murphy, Declan G.; Frydenberg, Mark; Hopkins, Julia F.; Bolton, Damien; Clouston, David; McPherson, John D.; Van Der Kwast, Theodorus; Boutros, Paul C.; Risbridger, Gail P.; Bristow, Robert G.

In: Nature Communications, Vol. 8, 13671, 09.01.2017.

Research output: Contribution to journalArticleResearchpeer-review

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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

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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.

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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.

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KW - cancer genomics

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