Homologous recombination DNA repair defects in PALB2-associated breast cancers

Abstract

Mono-allelic germline pathogenic variants in the <i>Partner And Localizer of BRCA2</i> (<i>PALB2</i>) 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 <i>PALB2</i>-associated breast cancers (BCs), and whether <i>PALB2</i>-associated BCs display bi-allelic inactivation of <i>PALB2</i> and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic <i>PALB2</i> germline mutations were analyzed by whole-exome sequencing (WES, <i>n</i> = 16) or targeted capture massively parallel sequencing (410 cancer genes, <i>n</i> = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the <i>PALB2</i> wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. <i>PALB2</i>-associated BCs were found to be heterogeneous at the genetic level, with <i>PIK3CA</i> (29%), <i>PALB2</i> (21%), <i>TP53</i> (21%), and <i>NOTCH3</i> (17%) being the genes most frequently affected by somatic mutations. Bi-allelic <i>PALB2</i> inactivation was found in 16 of the 24 cases (67%), either through LOH (<i>n</i> = 11) or second somatic mutations (<i>n</i> = 5) of the wild-type allele. High LST scores were found in all 12 <i>PALB2</i>-associated BCs with bi-allelic <i>PALB2</i> inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of <i>PALB2</i> was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic <i>PALB2</i> inactivation in <i>PALB2</i>-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of <i>PALB2</i>-associated BCs without <i>PALB2</i> bi-allelic inactivation lack genomic features of HRD.