A novel PALB2 truncating mutation in an Italian family with male breast cancer

Abstract

Abstract. Male breast cancer (MBC) is a rare disease, accounting for ~1% of all breast cancer cases worldwide. Although other genes are also involved, predisposing genetic factors to MBC include germline mutations in the BRCA genes (BRCA2). Among the other genes, partner and localizer of BRCA2 (PALB2) is considered a moderate-penetrance breast cancer susceptibility gene that may also play a role in MBC predisposition. Thus, the aim of the present study was to determine the PALB2 gene status in 8 MBC cases selected from a cohort of 181 hereditary breast and/or ovarian cancer probands. We performed PALB2 mutational analysis by direct sequencing of 13 exons and adjacent intronic regions. This study showed the presence of a PALB2 truncating mutation in 1/8 (12.5%) cases. This novel mutation was named c.1285_1286delAinsTC (p.I429SfsX12) and is localized in exon 4 of PALB2, in the region encoding for the ChAM motif which is important for the efficient association of PALB2 to chromatin and for recruitment of the BRCA complex to accumulate RAD51 at double-strand break sites. Our findings indicate that PALB2 could be added to the list of breast cancer susceptibility genes also in families with MBC cases.

Whole‐exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene

“…Our data show that MBC cases harboring PALB2 mutations were also affected by other tumors, including melanoma, prostate cancer, and lung cancer, and they had a FH of breast and other cancers, including stomach cancer. PALB2 mutations were frequently observed in pedigrees with cases of melanoma, pancreatic cancer, prostate cancer, lung cancer, and stomach cancer in addition to BC . Overall, these observations suggest that PALB2 ‐related families may resemble BRCA2 ‐like families, in which MBC and several other cancers may be found in addition to FBC.…”

“…PALB2 mutations were frequently observed in pedigrees with cases of melanoma, pancreatic cancer, prostate cancer, lung cancer, and stomach cancer in addition to BC. [25][26][27][28][29][30][31]34,36 Overall, these observations suggest that PALB2-related families may resemble BRCA2-like families, in which MBC and several other cancers may be found in addition to FBC. However, further studies are needed to evaluate the risk conferred by PALB2 mutations in cancers other than BC.…”

“…[26][27][28][31][32][33][34] Previous studies, including a small number of high-risk MBC cases (up to 13 cases), showed a variable mutation frequency ranging from 1% to 16%. 26,28,31,34 Our data, based on a series of high-risk MBC cases larger than those analyzed thus far, provide a more precise assessment of the contribution of PALB2 mutations in highrisk MBC cases. Notably, the frequency of PALB2 pathogenic mutations in high-risk MBC cases reported here was higher than that observed in high-risk FBC cases (ie, 4% vs 1%).…”

“…To date, only a limited number of studies have investigated the presence of PALB2 mutations in MBC . Previous studies, including a small number of high‐risk MBC cases (up to 13 cases), showed a variable mutation frequency ranging from 1% to 16% .…”

Regulation of sex hormone receptors in sexual dimorphism of human cancers

“…1), 24 of them are sex-dimorphic and all have statistically significant incidence differences between men and women, two types are men-specific (prostate cancer and testicular cancer), and four types of cancers are women-specific (breast cancer, cancer of the cervix uteri, cancer of the corpus and uterus, NOS, and ovarian cancer). Although males have a rare occurrence of breast cancer [5, 6], we considered breast cancer as female-specific because mammary glands are barely developed in men. For all 24 sex-dimorphic cancers, 23 of them are male-dominant, and interestingly, only one cancer, thyroid cancer, is female-dominant.…”