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

Abstract

Purpose: Monoallelic germ-line deleterious mutations of PALB2 (partner and localizer of BRCA2) are associated with breast cancer risk and have been found in several populations, with carrier frequencies of ~1−2%. Initially, these mutations were considered to have moderate penetrance, but accumulating evidence now indicates that they are associated with much higher risk. Methods:In this study, we sequenced the PALB2 coding regions unlinked to BRCA (breast cancer) genes in 575 probands from Italian breast cancer families recruited in Milan. results:We found 12 carriers (2.1%) of deleterious mutations, and none of the mutations was found in 784 controls collected in Milan.One of these mutations, the c.1027C>T (p.Gln343X), was found to be recurrent in the province of Bergamo in northern Italy, being detected in 6/113 (5.3%) familial breast cancer cases and 2/477 (0.4%) controls recruited in this area (Fisher's exact test: P < 0.01).conclusions: Our data provide confirmatory findings that, in the Italian population also, deleterious mutations of PALB2 are relatively frequent predisposing factors for breast cancer and may be associated with high risk of the disease.

The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk

“…These two studies [2, 3] together identified the p.Leu939Trp mutation in 10/1741 (0.57 %) women with breast cancer and 8/1534 (0.52 %) unaffected controls, suggesting that this mutation is not associated with breast cancer risk. Further, we later published a third study corroborating this null finding [4] and have subsequently reported additional evidence that the p.Leu939Trp mutation is not associated with breast cancer risk, based on genotyping of 42,671 breast cancer cases and 42,164 controls (odds ratio = 1.05, 95 % confidence interval = 0.83–1.32, p value = 0.70) [5]. Finally, we observed that the p.Leu939Trp mutation does not disrupt the HR-mediated DNA repair activity of PALB2 (Fig.…”

Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2

“…PALB2 mutations were previously identified through Sanger sequencing or targeted next generation sequencing ([4, 7]; Weitzel/Neuhausen personal communication). When available, relatives of PALB2 mutation carriers were genotyped for their family-specific mutations by Sanger sequencing using primers previously described [4, 8].…”

“…and it is ncluded on clinical multigene breast cancer panels. We had previously identified a recurrent mutation – the c.1027C>T (p.Gln343*) in Northern Italy; it was detected in 6 of 113 familial cases and 2 of 477 controls all from the Bergamo province [4]. A second PALB2 mutation, c.2167_2168delAT (p.Met723Valfs*21), has been identified multiple times in individuals from geographically diverse areas by independent research groups.…”

“…A second PALB2 mutation, c.2167_2168delAT (p.Met723Valfs*21), has been identified multiple times in individuals from geographically diverse areas by independent research groups. This mutation was found in an Italian and an Italian-American families, three Hispanic probands from Southern California, and a Nigerian proband ([4–6]; S. Neuhausen/J. Weitzel, personal communications; F. Olopade, personal communication).…”

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]. Inconsistent conclusions may be due to small sample sizes in previous studies with inadequate statistical power for complex traits.…”