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 journalArticlepeer-review

33 Citations (Scopus)
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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 languageEnglish
Article number23
Pages (from-to)1-14
Number of pages14
Journalnpj Breast Cancer
Issue number1
Early online date8 Aug 2019
Publication statusPublished - 23 Nov 2019
Externally publishedYes

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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