BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases

Abstract

Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included in this study, carried the CHEK2 1100delC, IVS2+1G>A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy.

Gene copy number variation in male breast cancer by aCGH

“…The prevalence of MBC increases with age and its susceptibility may result from rare mutations in high penetrance genes such as BRCA1 and BRCA2, in particular BRCA2 (4-40%) more than BRCA1 (4%) mutations [8]. Other genes seem to be involved in MBC such as PTEN which results mutated in 22% [31], and other low penetrance genes such as CHEK2, mutated in 9% of MBC cases [8]. In families with CHEK2*1100delC variant, the risk of MBC was reported as ten times greater than normal [8].…”

“…Other genes seem to be involved in MBC such as PTEN which results mutated in 22% [31], and other low penetrance genes such as CHEK2, mutated in 9% of MBC cases [8]. In families with CHEK2*1100delC variant, the risk of MBC was reported as ten times greater than normal [8]. Interestingly, the contribution of the CHEK2*1100delC mutation to BC predisposition varies by ethnic group and from country to country [4,14].…”

The BRCAPRO 5.0 model is a useful tool in genetic counseling and clinical management of male breast cancer cases

“…The recruitment of the cases and the BRCA1/2 mutational analysis were carried out as recently described. 16,17 Briefly, the recruitment of all incident MBC cases was based on all currently available local sources (including pathology departments and the hospital discharge database). For each case index the entire coding sequence and each intron-exon boundary were screened for germline mutations by combining the protein truncation test (PTT), single-strand conformation polymorphism (SSCP), multiplex ligation-dependent probe amplification (MLPA) and direct sequencing.…”

A novel germline CHEK2 deletion truncating the kinase domain identified in a French family with high-risk of breast/ovarian cancer

“…The c.1100DelC CHEK2 mutation frequency varies according to the population studied. The highest frequencies have been observed in Northern Europe (1-11%) probably caused by an common ancestral origin [14,15] but this variant is infrequent to absent in populations from Southern Europe including the Basque country (0.93%) [16], as well as the Spanish [17] or Italian [18] populations. The extremely low frequency of this mutation in our population coming from the south west of France confirms its weak relevance for the practical clinic in populations from Southern Europe.…”