Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer

Abstract

It has been demonstrated that monoallelic PALB2 (Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline PALB2 mutations presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline PALB2 mutations in a set of 131 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of PALB2 gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several PALB2 variants, but no other obvious deleterious PALB2 mutation has been found. Thus, our study does not support an enrichment of PALB2 germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the PALB2 gene.

PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo

“…7 Additional studies found carriers of truncating mutations with a frequency of ~1−2% in Spanish, Chinese, South African, Russian, German, Italian, AfricanAmerican, Australasian, and Malaysian familial or early-onset breast cancer cases. 10,[20][21][22][23][24] A similar frequency was observed in population-based studies of Australians and mixed-ethnicity breast cancer cases. 20,25,26 A mutation-carrier frequency of 3.4% was reported in familial cases from the United States.…”

Breast-Cancer Risk in Families With Mutations in PALB2

“…The question of whether loss-of-function mutations in PALB2 confer a predisposition to ovarian cancer will require larger studies to address. We also estimated that the risk of breast cancer for male PALB2 mutation carriers is increased by a factor of 8, which is consistent with previous reports, 7,35,36 but the confidence interval for this estimate was very large. PALB2 loss-of-function mutations have been shown to confer a predisposition to pancreatic cancer, 37,38 but the lifetime risk in carriers has yet to be quantified.…”

The PALB2 Gene Is a Strong Candidate for Clinical Testing in BRCA1- and BRCA2-Negative Hereditary Breast Cancer

“…Alu sequences were involved in all detected rearrangements. To date, a large rearrangement in PALB2 was detected only in a breast cancer family in Spain (28) and in a Canadian patient affected with breast and pancreatic cancer (35).…”