Homologous recombination DNA repair defects in PALB2-associated breast cancers

Anqi Li; Felipe C. Geyer; Pedro Blecua; Ju Youn Lee; Pier Selenica; David N. Brown; Fresia Pareja; Simon S. K. Lee; Rahul Kumar; Barbara Rivera; Rui Bi; Salvatore Piscuoglio; Hannah Y. Wen; John R. Lozada; Rodrigo Gularte-Mérida; Luca Cavallone; kConFab Investigators; Zoulikha Rezoug; Tu Nguyen-Dumont; Paolo Peterlongo; Carlo Tondini; Thorkild Terkelsen; Karina Rønlund; Susanne E. Boonen; Arto Mannerma; Robert Winqvist; Marketa Janatova; Pathmanathan Rajadurai; Bing Xia; Larry Norton; Mark E. Robson; Pei-Sze Ng; Lai Meng Looi; Melissa C. Southey; Britta Weigelt; Teo Soo-Hwang; Marc Tischkowitz; William D. Foulkes; Jorge S. Reis-Filho

doi:10.1038/s41523-019-0115-9

Homologous recombination DNA repair defects in PALB2-associated breast cancers

Anqi Li, Felipe C. Geyer, Pedro Blecua, Ju Youn Lee, Pier Selenica, David N. Brown, Fresia Pareja, Simon S. K. Lee, Rahul Kumar, Barbara Rivera, Rui Bi, Salvatore Piscuoglio, Hannah Y. Wen, John R. Lozada, Rodrigo Gularte-Mérida, Luca Cavallone, kConFab Investigators, Zoulikha Rezoug, Tu Nguyen-Dumont, Paolo PeterlongoCarlo Tondini, Thorkild Terkelsen, Karina Rønlund, Susanne E. Boonen, Arto Mannerma, Robert Winqvist, Marketa Janatova, Pathmanathan Rajadurai, Bing Xia, Larry Norton, Mark E. Robson, Pei-Sze Ng, Lai Meng Looi, Melissa C. Southey, Britta Weigelt, Teo Soo-Hwang, Marc Tischkowitz, William D. Foulkes, Jorge S. Reis-Filho^*

^*Corresponding author for this work

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

40 Citations (Scopus)

41 Downloads (Pure)

Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Original language	English
Article number	23
Pages (from-to)	1-14
Number of pages	14
Journal	npj Breast Cancer
Volume	5
Issue number	1
Early online date	8 Aug 2019
DOIs	https://doi.org/10.1038/s41523-019-0115-9 https://doi.org/10.1038/s41523-019-0140-8
Publication status	Published - 23 Nov 2019
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

In the original version of this paper, the link to the data record in the Data Availability Statement was incorrectly listed as https:// doi.org/10.6084/m9.figshare.8138912.44. The link has been corrected to https://doi.org/10.6084/m9.figshare.8138912. This has been corrected in the HTML and PDF versions of this article.

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10.1038/s41523-019-0115-9
10.1038/s41523-019-0140-8Licence: CC BY

Publisher version (open access)Final published version, 2.05 MBLicence: CC BY

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Li, A., Geyer, F. C., Blecua, P., Lee, J. Y., Selenica, P., Brown, D. N., Pareja, F., Lee, S. S. K., Kumar, R., Rivera, B., Bi, R., Piscuoglio, S., Wen, H. Y., Lozada, J. R., Gularte-Mérida, R., Cavallone, L., kConFab Investigators, Rezoug, Z., Nguyen-Dumont, T., ... Reis-Filho, J. S. (2019). Homologous recombination DNA repair defects in PALB2-associated breast cancers. npj Breast Cancer, 5(1), 1-14. Article 23. https://doi.org/10.1038/s41523-019-0115-9, https://doi.org/10.1038/s41523-019-0140-8

@article{568f8ac8644f4849b305d4290411089b,

title = "Homologous recombination DNA repair defects in PALB2-associated breast cancers",

abstract = "Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.",

author = "Anqi Li and Geyer, {Felipe C.} and Pedro Blecua and Lee, {Ju Youn} and Pier Selenica and Brown, {David N.} and Fresia Pareja and Lee, {Simon S. K.} and Rahul Kumar and Barbara Rivera and Rui Bi and Salvatore Piscuoglio and Wen, {Hannah Y.} and Lozada, {John R.} and Rodrigo Gularte-M{\'e}rida and Luca Cavallone and {kConFab Investigators} and Morteza Aghmesheh and David Amor and Leslie Andrews and Yoland Antill and Rosemary Balleine and Jonathan Beesley and Anneke Blackburn and Michael Bogwitz and Melissa Brown and Matthew Burgess and Jo Burke and Phyllis Butow and Liz Caldon and Ian Campbell and Alice Christian and Christine Clarke and Paul Cohen and Ashley Crook and James Cui and Margaret Cummings and Sarah-Jane Dawson and {De Fazio}, Anna and Martin Delatycki and Alex Dobrovic and Tracy Dudding and Pascal Duijf and Edward Edkins and Stacey Edwards and Gelareh Farshid and Andrew Fellows and Michael Field and James Flanagan and Peter Fong and John Forbes and Laura Forrest and Stephen Fox and Juliet French and Michael Friedlander and Ortega, {David Gallego} and Michael Gattas and Graham Giles and Grantley Gill and Margaret Gleeson and Sian Greening and Eric Haan and Marion Harris and Nick Hayward and Ian Hickie and John Hopper and Clare Hunt and Paul James and Mark Jenkins and Rick Kefford and Maira Kentwell and Judy Kirk and James Kollias and Sunil Lakhani and Geoff Lindeman and Lara Lipton and Lizz Lobb and Sheau Lok and Finlay Macrea and Graham Mann and Deb Marsh and Sue-Anne McLachlan and Bettina Meiser and Roger Milne and Sophie Nightingale and Shona O{\textquoteright}Connell and Nick Pachter and Briony Patterson and Kelly Phillips and Mona Saleh and Elizabeth Salisbury and Christobel Saunders and Jodi Saunus and Clare Scott and Rodney Scott and Adrienne Sexton and Andrew Shelling and Peter Simpson and Allan Spigelman and Mandy Spurdle and Jennifer Stone and Jessica Taylor and Heather Thorne and Alison Trainer and Georgia Trench and Kathy Tucker and Jane Visvader and Logan Walker and Mathew Wallis and Rachael Williams and Ingrid Winship and Kathy Wu and Young, {Mary Anne} and Zoulikha Rezoug and Tu Nguyen-Dumont and Paolo Peterlongo and Carlo Tondini and Thorkild Terkelsen and Karina R{\o}nlund and Boonen, {Susanne E.} and Arto Mannerma and Robert Winqvist and Marketa Janatova and Pathmanathan Rajadurai and Bing Xia and Larry Norton and Robson, {Mark E.} and Pei-Sze Ng and Looi, {Lai Meng} and Southey, {Melissa C.} and Britta Weigelt and Teo Soo-Hwang and Marc Tischkowitz and Foulkes, {William D.} and Reis-Filho, {Jorge S.}",

note = "Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. In the original version of this paper, the link to the data record in the Data Availability Statement was incorrectly listed as https:// doi.org/10.6084/m9.figshare.8138912.44. The link has been corrected to https://doi.org/10.6084/m9.figshare.8138912. This has been corrected in the HTML and PDF versions of this article.",

year = "2019",

month = nov,

day = "23",

doi = "10.1038/s41523-019-0115-9",

language = "English",

volume = "5",

pages = "1--14",

journal = "npj Breast Cancer",

issn = "2374-4677",

publisher = "Springer, Springer Nature",

number = "1",

}

Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Mérida, R, Cavallone, L, kConFab Investigators, Rezoug, Z, Nguyen-Dumont, T, Peterlongo, P, Tondini, C, Terkelsen, T, Rønlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, LM, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD & Reis-Filho, JS 2019, 'Homologous recombination DNA repair defects in PALB2-associated breast cancers', npj Breast Cancer, vol. 5, no. 1, 23, pp. 1-14. https://doi.org/10.1038/s41523-019-0115-9, https://doi.org/10.1038/s41523-019-0140-8

TY - JOUR

T1 - Homologous recombination DNA repair defects in PALB2-associated breast cancers

AU - Li, Anqi

AU - Geyer, Felipe C.

AU - Blecua, Pedro

AU - Lee, Ju Youn

AU - Selenica, Pier

AU - Brown, David N.

AU - Pareja, Fresia

AU - Lee, Simon S. K.

AU - Kumar, Rahul

AU - Rivera, Barbara

AU - Bi, Rui

AU - Piscuoglio, Salvatore

AU - Wen, Hannah Y.

AU - Lozada, John R.

AU - Gularte-Mérida, Rodrigo

AU - Cavallone, Luca

AU - kConFab Investigators

AU - Aghmesheh, Morteza

AU - Amor, David

AU - Andrews, Leslie

AU - Antill, Yoland

AU - Balleine, Rosemary

AU - Beesley, Jonathan

AU - Blackburn, Anneke

AU - Bogwitz, Michael

AU - Brown, Melissa

AU - Burgess, Matthew

AU - Burke, Jo

AU - Butow, Phyllis

AU - Caldon, Liz

AU - Campbell, Ian

AU - Christian, Alice

AU - Clarke, Christine

AU - Cohen, Paul

AU - Crook, Ashley

AU - Cui, James

AU - Cummings, Margaret

AU - Dawson, Sarah-Jane

AU - De Fazio, Anna

AU - Delatycki, Martin

AU - Dobrovic, Alex

AU - Dudding, Tracy

AU - Duijf, Pascal

AU - Edkins, Edward

AU - Edwards, Stacey

AU - Farshid, Gelareh

AU - Fellows, Andrew

AU - Field, Michael

AU - Flanagan, James

AU - Fong, Peter

AU - Forbes, John

AU - Forrest, Laura

AU - Fox, Stephen

AU - French, Juliet

AU - Friedlander, Michael

AU - Ortega, David Gallego

AU - Gattas, Michael

AU - Giles, Graham

AU - Gill, Grantley

AU - Gleeson, Margaret

AU - Greening, Sian

AU - Haan, Eric

AU - Harris, Marion

AU - Hayward, Nick

AU - Hickie, Ian

AU - Hopper, John

AU - Hunt, Clare

AU - James, Paul

AU - Jenkins, Mark

AU - Kefford, Rick

AU - Kentwell, Maira

AU - Kirk, Judy

AU - Kollias, James

AU - Lakhani, Sunil

AU - Lindeman, Geoff

AU - Lipton, Lara

AU - Lobb, Lizz

AU - Lok, Sheau

AU - Macrea, Finlay

AU - Mann, Graham

AU - Marsh, Deb

AU - McLachlan, Sue-Anne

AU - Meiser, Bettina

AU - Milne, Roger

AU - Nightingale, Sophie

AU - O’Connell, Shona

AU - Pachter, Nick

AU - Patterson, Briony

AU - Phillips, Kelly

AU - Saleh, Mona

AU - Salisbury, Elizabeth

AU - Saunders, Christobel

AU - Saunus, Jodi

AU - Scott, Clare

AU - Scott, Rodney

AU - Sexton, Adrienne

AU - Shelling, Andrew

AU - Simpson, Peter

AU - Spigelman, Allan

AU - Spurdle, Mandy

AU - Stone, Jennifer

AU - Taylor, Jessica

AU - Thorne, Heather

AU - Trainer, Alison

AU - Trench, Georgia

AU - Tucker, Kathy

AU - Visvader, Jane

AU - Walker, Logan

AU - Wallis, Mathew

AU - Williams, Rachael

AU - Winship, Ingrid

AU - Wu, Kathy

AU - Young, Mary Anne

AU - Rezoug, Zoulikha

AU - Nguyen-Dumont, Tu

AU - Peterlongo, Paolo

AU - Tondini, Carlo

AU - Terkelsen, Thorkild

AU - Rønlund, Karina

AU - Boonen, Susanne E.

AU - Mannerma, Arto

AU - Winqvist, Robert

AU - Janatova, Marketa

AU - Rajadurai, Pathmanathan

AU - Xia, Bing

AU - Norton, Larry

AU - Robson, Mark E.

AU - Ng, Pei-Sze

AU - Looi, Lai Meng

AU - Southey, Melissa C.

AU - Weigelt, Britta

AU - Soo-Hwang, Teo

AU - Tischkowitz, Marc

AU - Foulkes, William D.

AU - Reis-Filho, Jorge S.

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. In the original version of this paper, the link to the data record in the Data Availability Statement was incorrectly listed as https:// doi.org/10.6084/m9.figshare.8138912.44. The link has been corrected to https://doi.org/10.6084/m9.figshare.8138912. This has been corrected in the HTML and PDF versions of this article.

PY - 2019/11/23

Y1 - 2019/11/23

N2 - Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

AB - Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

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Homologous recombination DNA repair defects in PALB2-associated breast cancers

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