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

Homologous recombination DNA repair defects in PALB2-associated breast cancers Journal Article

Authors:	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.; Peterlongo, P.; Tondini, C.; Terkelsen, T.; Rønlund, K.; Boonen, S. E.; Mannerma, A.; Winqvist, R.; Janatova, M.; Rajadurai, P.; Xia, B.; Norton, L.; Robson, M. E.; Ng, P. S.; Looi, L. M.; Southey, M. C.; Weigelt, B.; Soo-Hwang, T.; Tischkowitz, M.; Foulkes, W. D.; Reis-Filho, J. S.
Article 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. © 2019, The Author(s).
Journal Title:	npj Breast Cancer
Volume:	5
ISSN:	2374-4677
Publisher:	Nature Publishing Group
Date Published:	2019-08-08
Start Page:	23
Language:	English
DOI:	10.1038/s41523-019-0115-9
PROVIDER:	scopus
PMCID:	PMC6687719
PUBMED:	31428676
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85070388252&doi=10.1038%2fs41523-019-0115-9&partnerID=40&md5=2b6a21b6cd5c46c94389cfb1ed4f4058
Notes:	Correction issued, see DOI: 10.1038/s41523-019-0140-8 -- Article -- Source: Scopus