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: | |
| Notes: | Article -- Export Date: 4 September 2019 -- Source: Scopus |
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