Molecular analysis of PALB2‐associated breast cancers

Abstract

PALB2 is established as the most clinically important moderate to high penetrance breast cancer predisposition gene after BRCA1 and BRCA2. Mutations in classical familial cancer predisposition genes are presumed to be recessive at the cellular level and therefore a second inactivating somatic mutation is required in the tumour tissue. However, from the limited data that exist, PALB2 may be an example of a cancer predisposition gene that does not conform to Knudson's 'two hit' paradigm. We conducted genome-wide copy number analysis and targeted sequencing of PALB2 and other breast cancer driver genes in 15 invasive breast cancers from individuals carrying pathogenic germline mutations in PALB2. The majority of cancers showed clear evidence of bi-allelic inactivation of PALB2 (10/15) either as loss of heterozygosity involving the wild-type allele (six tumours) or as somatic point mutations (four tumours). All PALB2-null cancers had high homologous recombination deficiency (HRD) scores consistent with a homologous recombination repair deficiency. Interestingly, all but one of the PALB2 heterozygous cancers also had high HRD scores, suggesting that alternative mechanisms of PALB2 functional loss might be operating in these cancers. Our findings demonstrate that PALB2 does undergo bi-allelic inactivation in the majority of breast cancers from PALB2 germline mutation carriers. This feature has implications for the discovery of new moderate to high penetrance breast cancer predisposition genes as it supports using the existence of a 'second hit' and mutation signatures as important search criteria. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

“…While wild‐type PALB2 partly complemented PALB2 siRNA‐treated cells, PALB2 p.M296Nfs mutant did not rescue HRR capacity (Fig D). Furthermore, overexpression of PALB2 p.M296Nfs mutant led to a two‐fold reduction in mClover‐positive cells, demonstrating that PALB2 p.M296Nfs leads to HRR deficiency despite the presence of endogenous wild‐type PALB2, in favor of a dominant negative effect (Fig E; Lee et al , ). Collectively, both sequencing and functional assays indicate that HRR deficiency in PDX093 is due to the PALB2 c.886dupA mutation.…”

“…In these patients, the RAD51 assay could be used as an enrichment biomarker to better predict sensitivity to PARPi, since restoration of the HRR pathway might have occurred and result in PARPi resistance (Konstantinopoulos et al , ; Cruz et al , ). Second, tumors with somatic alterations in HRR‐related genes, such as the PALB2 mutations described in 4% of metastatic BC (Lefebvre et al , ; Lee et al , ). And third, tumors with epigenetic HRR silencing, such as BRCA1 promoter hypermethylation.…”

The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

“…Cases of pure IDP with sufficient DNA available (n = 9/24) were sequenced using a targeted gene panel (258 genes 27,29 ) (Supplementary Table 1) to identify driver somatic mutations (Fig. 3).…”

Association between rs120963, rs152451, rs249935, rs447529, rs8053188, and rs16940342 Polymorphisms in the <b><i>PALB2</i></b> Gene and Breast Cancer Susceptibility: A Meta-Analysis

“…PALB2 , which is located on chromosome 16p12.1, is established as the third clinically important moderate-to-high penetrance breast cancer predisposition gene after BRCA1 and BRCA2 [2]. Many studies have reported the role of PALB2 polymorphisms in several loci with regard to breast cancer risk in the past decade, however with conflicting results [3,4,5,6].…”