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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MSK Authors
  1. Larry Norton
    626 Norton
  2. Mark E Robson
    409 Robson
  3. Yong Hannah Wen
    141 Wen
  4. Britta Weigelt
    300 Weigelt
  5. Jorge Sergio Reis
    328 Reis
  6. Anqi Li
    14 Li
  7. John Roy Lozada
    16 Lozada
  8. Rui Bi
    7 Bi
  9. Rahul Kumar
    20 Kumar
  10. Ju Youn Lee
    11 Lee
  11. David Norman Brown
    27 Brown
  12. Simon Lee
    1 Lee