Compromised BRCA1–PALB2 interaction is associated with breast cancer risk

Abstract

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretations of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here, we report on the identification of a novel PALB2 variant, c.104T>C [p.L35P], that segregated in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression.

Molecular analysis of PALB2‐associated breast cancers

“…The strongest evidence to date of a bi‐allelic inactivation requirement for PALB2 is from analysis of a single PALB2 tumour where exome sequencing identified a somatic nonsense mutation, presumably in the wild‐type allele. This tumour also showed a very high LST score and a mutation signature 3, both consistent with loss of homologous DNA repair capacity . However, none of the other studies performed full exon sequencing of PALB2 .…”

“…Mutation signatures were also assessed based on 110 SNVs identified in PALB2 germline mutation tumours (43 SNVs among the HET group and 67 among the NULL group) and 225 SNVs among the 35 sporadic breast tumours. The PALB2 tumours, but not the sporadic tumours, showed a prominent somatic mutation signature 3 (36.5% versus 0%) consistent with defective homologous recombination [13,28,38] (supplementary material, Figure S2). Because of the small number of mutations, it was not possible to derive reliable signatures for the PALB2 heterozygous and PALB2-null tumours separately.…”

BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

“…BRCA1 promotes the displacement of 53BP1 from chromatin surrounding DSBs and consequently activates DNA end resection (Chapman et al, 2012; Densham et al, 2016). After DNA end resection, BRCA1 directly interacts with and recruits PALB2 to DSB sites, where BRCA2-RAD51 form s a com plex with PALB2, and mutations that block the BRCA1-PALB2 interaction have been shown to reduce the efficiency of RAD51 foci formation and HR (Anantha et al, 2017; Foo et al, 2017; Sy et al, 2009). …”

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

“…PALB2 is a binding partner of BRCA1 and also an essential protein for the normal function of BRCA2 during repair of DNA double stranded breaks . A recent study has identified that defective PALB2‐BRCA1 interaction is associated with increased BC risk . California Teachers Study, a nested case–control study (1,353 cases and 1,384 controls), identified several single nucleotide polymorphisms (SNPs) in apoptosis initiator CASP8 that were associated with BC risk, while SNP rs2293554 of CASP8 was specifically associated with HER2 + BC (OR = 1.98, 95% CI 1.34–2.92) .…”

“…22 A recent study has identified that defective PALB2-BRCA1 interaction is associated with increased BC risk. 23 California Teachers Study, a nested case-control study (1,353 cases and 1,384 controls), identified several single nucleotide polymorphisms (SNPs) in apoptosis initiator CASP8 that were associated with BC risk, while SNP rs2293554 of CASP8 was specifically associated with HER2 1 BC (OR 5 1.98, 95% CI 1.34-2.92). 24 The combined loss of TP53 and PTEN leads to accelerated development of BC that is dependent on eukaryotic elongation factor-2 kinase (eEF2K).…”