A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

Paz Polak; Jaegil Kim; Lior Z. Braunstein; Rosa Karlic; Nicholas J. Haradhavala; Grace Tiao; Daniel Rosebrock; Dimitri Livitz; Kirsten Kübler; Kent W. Mouw; Atanas Kamburov; Yosef E. Maruvka; Ignaty Leshchiner; Eric S. Lander; Todd R. Golub; Aviad Zick; Alexandre Orthwein; Michael S. Lawrence; Rajbir N. Batra; Carlos Caldas; Daniel A. Haber; Peter W. Laird; Hui Shen; Leif W. Ellisen; Alan D. D'Andrea; Stephen J. Chanock; William D. Foulkes; Gad Getz

doi:10.1038/ng.3934

A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

Paz Polak
, Jaegil Kim
, Lior Z. Braunstein
, Rosa Karlic
, Nicholas J. Haradhavala
, Grace Tiao
, Daniel Rosebrock
, Dimitri Livitz
, Kirsten Kübler
, Kent W. Mouw
, Atanas Kamburov
, Yosef E. Maruvka
, Ignaty Leshchiner
, Eric S. Lander
, Todd R. Golub
, Aviad Zick
, Alexandre Orthwein
, Michael S. Lawrence
, Rajbir N. Batra
, Carlos Caldas

Daniel A. Haber, Peter W. Laird, Hui Shen, Leif W. Ellisen, Alan D. D'Andrea, Stephen J. Chanock, William D. Foulkes, Gad Getz

Broad Institute
Massachusetts General Hospital
Harvard University
Memorial Sloan-Kettering Cancer Center
University of Zagreb
Brigham and Women’s Hospital
Massachusetts Institute of Technology
Dana-Farber Cancer Institute
Hadassah University Medical Centre
McGill University
University of Cambridge
Cancer Research UK
Van Andel Institute
National Institutes of Health
McGill University

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

417 Scopus citations

Abstract

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ~1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

Original language	English
Pages (from-to)	1476-1486
Number of pages	11
Journal	Nature Genetics
Volume	49
Issue number	10
DOIs	https://doi.org/10.1038/ng.3934
State	Published - 1 Oct 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/ng.3934

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Polak, P., Kim, J., Braunstein, L. Z., Karlic, R., Haradhavala, N. J., Tiao, G., Rosebrock, D., Livitz, D., Kübler, K., Mouw, K. W., Kamburov, A., Maruvka, Y. E., Leshchiner, I., Lander, E. S., Golub, T. R., Zick, A., Orthwein, A., Lawrence, M. S., Batra, R. N., ... Getz, G. (2017). A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nature Genetics, 49(10), 1476-1486. https://doi.org/10.1038/ng.3934

@article{6182f0e9efb44e859e69234e98953498,

title = "A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer",

abstract = "Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing \textasciitilde{}1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.",

author = "Paz Polak and Jaegil Kim and Braunstein, \{Lior Z.\} and Rosa Karlic and Haradhavala, \{Nicholas J.\} and Grace Tiao and Daniel Rosebrock and Dimitri Livitz and Kirsten K{\"u}bler and Mouw, \{Kent W.\} and Atanas Kamburov and Maruvka, \{Yosef E.\} and Ignaty Leshchiner and Lander, \{Eric S.\} and Golub, \{Todd R.\} and Aviad Zick and Alexandre Orthwein and Lawrence, \{Michael S.\} and Batra, \{Rajbir N.\} and Carlos Caldas and Haber, \{Daniel A.\} and Laird, \{Peter W.\} and Hui Shen and Ellisen, \{Leif W.\} and D'Andrea, \{Alan D.\} and Chanock, \{Stephen J.\} and Foulkes, \{William D.\} and Gad Getz",

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Polak, P, Kim, J, Braunstein, LZ, Karlic, R, Haradhavala, NJ, Tiao, G, Rosebrock, D, Livitz, D, Kübler, K, Mouw, KW, Kamburov, A, Maruvka, YE, Leshchiner, I, Lander, ES, Golub, TR, Zick, A, Orthwein, A, Lawrence, MS, Batra, RN, Caldas, C, Haber, DA, Laird, PW, Shen, H, Ellisen, LW, D'Andrea, AD, Chanock, SJ, Foulkes, WD & Getz, G 2017, 'A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer', Nature Genetics, vol. 49, no. 10, pp. 1476-1486. https://doi.org/10.1038/ng.3934

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AU - Polak, Paz

AU - Kim, Jaegil

AU - Braunstein, Lior Z.

AU - Karlic, Rosa

AU - Haradhavala, Nicholas J.

AU - Tiao, Grace

AU - Rosebrock, Daniel

AU - Livitz, Dimitri

AU - Kübler, Kirsten

AU - Mouw, Kent W.

AU - Kamburov, Atanas

AU - Maruvka, Yosef E.

AU - Leshchiner, Ignaty

AU - Lander, Eric S.

AU - Golub, Todd R.

AU - Zick, Aviad

AU - Orthwein, Alexandre

AU - Lawrence, Michael S.

AU - Batra, Rajbir N.

AU - Caldas, Carlos

AU - Haber, Daniel A.

AU - Laird, Peter W.

AU - Shen, Hui

AU - Ellisen, Leif W.

AU - D'Andrea, Alan D.

AU - Chanock, Stephen J.

AU - Foulkes, William D.

AU - Getz, Gad

PY - 2017/10/1

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AB - Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ~1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

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A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

Abstract

Bibliographical note

UN SDGs

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