In:
npj Breast Cancer, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2019-08-08)
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
2374-4677
DOI:
10.1038/s41523-019-0115-9
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2019
ZDB Id:
2843288-5
