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.
Highlights
The Partner And Localizer of BRCA2 (PALB2) is a key protein that interacts with BRCA1 and BRCA2 and plays pivotal roles in homologous recombination (HR) DNA repair.[1]
The proportion of cases displaying a mutational signature 3 was significantly higher in the 12 PALB2-associated breast cancers with bi-allelic inactivation sequenced by whole-exome sequencing (WES) than in the 491 estrogen receptor (ER)−/HER2− and ER+/HER2− non-BRCA1/2/PALB2-associated breast cancers for which mutational signatures could be inferred (67% vs. 17%; P = 0.0002, Fisher’s exact test; P = 0.02, bootstrapping-corrected; Fig. 4c). These results suggest that PALB2-associated breast cancers with bi-allelic inactivation are more often HR-deficient than non-BRCA1/
We demonstrate that PALB2-associated breast cancers constitute a heterogeneous group of tumors at the genetic level and can be stratified according to the bi-allelic inactivation of the PALB2 wild-type allele
Summary
The Partner And Localizer of BRCA2 (PALB2) is a key protein that interacts with BRCA1 and BRCA2 and plays pivotal roles in homologous recombination (HR) DNA repair.[1] Bi-allelic PALB2 germline mutations (i.e., affecting both parental alleles of PALB2) cause Fanconi anemia,[2] whereas mono-allelic PALB2 germline mutations result in increased risk of breast, pancreatic and ovarian cancer.[3,4,5] The frequency of PALB2 germline mutations in familial breast cancer ranges from 0.6% to 2.7%,4 and the average cumulative breast cancer risk in PALB2 germline mutation carriers by the age of 70 years is ~35%,4 similar to that conferred by BRCA2 germline mutations.[6] Akin to sporadic and BRCA2 breast cancers, PALB2-associated breast cancers are heterogeneous in terms of their clinicopathologic features, being predominantly estrogen receptor (ER)-positive.[4] As compared to non-PALB2 mutation carriers, patients with PALB2 germline mutations have been reported to display a shorter 10-year survival.[7] Consistent with the role of PALB2 in HR DNA repair, PALB2-deficient cells have
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