Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Abstract

PALB2 (partner and localizer of BRCA2), as indicated by its name, is a BRCA2-interacting protein that plays an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair. While pathogenic variants of PALB2 have been well proven to confer an increased risk of breast cancer, data on its involvement in prostate cancer (PrC) have not been clearly demonstrated. We investigated, using targeted next generation sequencing (NGS), a 59-year-old Caucasian man who developed synchronous breast and prostate cancers. This genetic investigation allowed to identify an intragenic germline heterozygous duplication in PALB2, implicating intronic repetitive sequences spanning exon 11. This variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints have been identified and characterized at the nucleotide level (c.3114-811_3202-1756dup) using an approach based on walking PCR, long range PCR, and Sanger sequencing. RT-PCR using mRNA extracted from lymphocytes and followed by Sanger sequencing revealed a tandem duplication r.3114_3201dup; p.(Gly1068Glufs * 14). This duplication results in the synthesis of a truncated, and most-likely, non-functional protein. These findings expand the phenotypic spectrum of PALB2 variants and may improve the yield of genetic diagnoses in this field.

Pleomorphic/solid lobular carcinoma of male breast with PALB2 germline mutation: case report and literature review

“…In a recent Italian study, PALB2 represented the most frequently mutated gene (1.2%) among 503 non- BRCA1-2 MBC patients 30 . PALB2 is localized on chromosome 16p12.2 and encodes a protein that has an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair 31 . The estimated risk for MBC by the age 80 in PALB2 mutation carriers has been reported to be 1% compared with a general population risk of less than 0.1% 32 .…”

“…Another group described PALB2 gene alterations in BRCA1 and BRCA2 negative hereditary breast cancer, and one of the mutations identified was the p.R414X variants 39 , which was also described by Casadei et al in a series of familial breast cancer 40 . Another tumor in which this germline mutation has been highlighted is serous ovarian cancer, associated with other variants of the same gene and with mutations in other genes like BRCA1, BRCA2, CHEK2, BRIP1, BLM, MAP3K15, and PTPRH 41 .To date, PALB2 c.1240C > T has never been described in the literature in male breast cancer patients where other truncating PALB2 mutations are reported 7 , 31 .…”

Mutational spectrum of DNA damage and mismatch repair genes in prostate cancer

“…The authors of this study are aware of new results linking PALB2 to a statistically significant increase in the chance of developing PCa ( Yang et al, 2020 ). While it has long been known that these polymorphisms increase the risk of breast cancer, data on PALB2 ’s role in PCa have also been decisively proven ( Horak et al, 2019 ; Wokołorczyk et al, 2020 ; Bouras et al, 2022 ).…”