Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Robert W. Mutter; Nadeem Riaz; Charlotte K.Y. Ng; Rob Delsite; Salvatore Piscuoglio; Marcia Edelweiss; Luciano G. Martelotto; Rita A. Sakr; Tari A. King; Dilip D. Giri; Maria Drobnjak; Edi Brogi; Ranjit Bindra; Giana Bernheim; Raymond S. Lim; Pedro Blecua; Alexis Desrichard; Dan Higginson; Russell Towers; Ruomu Jiang; William Lee; Britta Weigelt; Jorge S. Reis-Filho; Simon N. Powell

doi:10.1002/path.4890

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Robert W. Mutter, Nadeem Riaz, Charlotte K.Y. Ng, Rob Delsite, Salvatore Piscuoglio, Marcia Edelweiss, Luciano G. Martelotto, Rita A. Sakr, Tari A. King, Dilip D. Giri, Maria Drobnjak, Edi Brogi, Ranjit Bindra, Giana Bernheim, Raymond S. Lim, Pedro Blecua, Alexis Desrichard, Dan Higginson, Russell Towers, Ruomu JiangWilliam Lee, Britta Weigelt, Jorge S. Reis-Filho, Simon N. Powell

Medical Oncology

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

27 Scopus citations

Abstract

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects.

Original language	English (US)
Pages (from-to)	165-177
Number of pages	13
Journal	Journal of Pathology
Volume	242
Issue number	2
DOIs	https://doi.org/10.1002/path.4890
State	Published - Jun 2017

Keywords

BRCAness
DNA repair
RAD51
homologous recombination-deficient
mutation

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1002/path.4890

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Mutter, R. W., Riaz, N., Ng, C. K. Y., Delsite, R., Piscuoglio, S., Edelweiss, M., Martelotto, L. G., Sakr, R. A., King, T. A., Giri, D. D., Drobnjak, M., Brogi, E., Bindra, R., Bernheim, G., Lim, R. S., Blecua, P., Desrichard, A., Higginson, D., Towers, R., ... Powell, S. N. (2017). Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer. Journal of Pathology, 242(2), 165-177. https://doi.org/10.1002/path.4890

Mutter, RW, Riaz, N, Ng, CKY, Delsite, R, Piscuoglio, S, Edelweiss, M, Martelotto, LG, Sakr, RA, King, TA, Giri, DD, Drobnjak, M, Brogi, E, Bindra, R, Bernheim, G, Lim, RS, Blecua, P, Desrichard, A, Higginson, D, Towers, R, Jiang, R, Lee, W, Weigelt, B, Reis-Filho, JS & Powell, SN 2017, 'Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer', Journal of Pathology, vol. 242, no. 2, pp. 165-177. https://doi.org/10.1002/path.4890

@article{d0066fe14b154fbfb074d878e6661de1,

title = "Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer",

abstract = "Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects.",

keywords = "BRCAness, DNA repair, RAD51, homologous recombination-deficient, mutation",

author = "Mutter, {Robert W.} and Nadeem Riaz and Ng, {Charlotte K.Y.} and Rob Delsite and Salvatore Piscuoglio and Marcia Edelweiss and Martelotto, {Luciano G.} and Sakr, {Rita A.} and King, {Tari A.} and Giri, {Dilip D.} and Maria Drobnjak and Edi Brogi and Ranjit Bindra and Giana Bernheim and Lim, {Raymond S.} and Pedro Blecua and Alexis Desrichard and Dan Higginson and Russell Towers and Ruomu Jiang and William Lee and Britta Weigelt and Reis-Filho, {Jorge S.} and Powell, {Simon N.}",

note = "Funding Information: We would like to thank Mesruh Turkekul and Katia Monova for their help with immunohistochemical staining. The sequencing core facility is supported by the Cancer Center Support Grant of the National Institutes of Health (grant No P30CA008748). SNP and JSR were funded in part by the Geoffrey Beene Cancer Center. SP was funded in part by a Susan G Komen Postdoctoral Fellowship Grant (PDF14298348). RWM is supported by P50 CA116201 Mayo Clinic Breast Cancer SPORE and the American Society for Radiation Oncology. Publisher Copyright: Copyright {\textcopyright} 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2017",

month = jun,

doi = "10.1002/path.4890",

language = "English (US)",

volume = "242",

pages = "165--177",

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issn = "0022-3417",

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T1 - Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

AU - Mutter, Robert W.

AU - Riaz, Nadeem

AU - Ng, Charlotte K.Y.

AU - Delsite, Rob

AU - Piscuoglio, Salvatore

AU - Edelweiss, Marcia

AU - Martelotto, Luciano G.

AU - Sakr, Rita A.

AU - King, Tari A.

AU - Giri, Dilip D.

AU - Drobnjak, Maria

AU - Brogi, Edi

AU - Bindra, Ranjit

AU - Bernheim, Giana

AU - Lim, Raymond S.

AU - Blecua, Pedro

AU - Desrichard, Alexis

AU - Higginson, Dan

AU - Towers, Russell

AU - Jiang, Ruomu

AU - Lee, William

AU - Weigelt, Britta

AU - Reis-Filho, Jorge S.

AU - Powell, Simon N.

N1 - Funding Information: We would like to thank Mesruh Turkekul and Katia Monova for their help with immunohistochemical staining. The sequencing core facility is supported by the Cancer Center Support Grant of the National Institutes of Health (grant No P30CA008748). SNP and JSR were funded in part by the Geoffrey Beene Cancer Center. SP was funded in part by a Susan G Komen Postdoctoral Fellowship Grant (PDF14298348). RWM is supported by P50 CA116201 Mayo Clinic Breast Cancer SPORE and the American Society for Radiation Oncology. Publisher Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2017/6

Y1 - 2017/6

N2 - Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects.

AB - Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects.

KW - BRCAness

KW - DNA repair

KW - RAD51

KW - homologous recombination-deficient

KW - mutation

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IS - 2

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Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Abstract

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