DNA methylation variations in familial female and male breast cancer

Abstract

In total, ~25% of familial breast cancer (BC) is attributed to germline mutations of the BRCA1 and BRCA2 genes, while the rest of the cases are included in the BRCAX group. BC is also known to affect men, with a worldwide incidence of 1%. Epigenetic alterations, including DNA methylation, have been rarely studied in male breast cancer (MBC) on a genome-wide level. The aim of the present study was to examine the global DNA methylation profiles of patients with BC to identify differences between familial female breast cancer (FBC) and MBC, and according to BRCA1, BRCA2 or BRCAX mutation status. The genomic DNA of formalin-fixed paraffin-embedded tissues from 17 women and 7 men with BC was subjected to methylated DNA immunoprecipitation and hybridized on human promoter microarrays. The comparison between FBC and MBC revealed 2,846 significant differentially methylated regions corresponding to 2,486 annotated genes. Gene Ontology enrichment analysis revealed molecular function terms, such as the GTPase superfamily genes (particularly the GTPase Rho GAP/GEF and GTPase RAB), and cellular component terms associated with cytoskeletal architecture, such as ‘cytoskeletal part’, ‘keratin filament’ and ‘intermediate filament’. When only FBC was considered, several cancer-associated pathways were among the most enriched KEGG pathways of differentially methylated genes when the BRCA2 group was compared with the BRCAX or BRCA1+BRCAX groups. The comparison between the BRCA1 and BRCA2+BRCAX groups comprised the molecular function term ‘cytoskeletal protein binding’. Finally, the functional annotation of differentially methylated genes between the BRCAX and BRCA1+BRCA2 groups indicated that the most enriched molecular function terms were associated with GTPase activity. In conclusion, to the best of our knowledge, the present study was the first to compare the global DNA methylation profile of familial FBC and MBC. The results may provide useful insights into the epigenomic subtyping of BC and shed light on a possible novel molecular mechanism underlying BC carcinogenesis.

Clinicopathological features, genetic alterations, and BRCA1 promoter methylation in Japanese male patients with breast cancer

“…Methylation of the BRCA1 promoter region is known to be one of the causes of breast cancer development in women [ 29 ] and has been reported as an oncogenic mechanism in familial breast cancer [ 30 ], but it was not detected in this study. It is possible that methylation of the BRCA1 promoter region does not contribute to carcinogenesis in Japanese patients with MBC; however, due to the small number of samples analyzed in this study, we cannot draw such a conclusion with certainty.…”

Analysis of the distinct features of metastasis male breast cancer and its effect on overall survival based on the SEER database compared with female breast cancer

“…Hong et al from South Korea theorized that the long gap between symptom onset and diagnosis was the main reason for the difference in the rate of occurrence of distant metastasis between MBC and FBC ( 17 ). Campos et al reported that BRCA1 and BRCA2 gene mutations were closely related to the occurrence of MBC ( 18 ), while Abeni et al demonstrated significant differences in DNA methylation between MBC and FBC in GTPase Rho GAP/GEF , GTPase RAB , BRCAX , BRCA1 + BRCAX , and other genes ( 19 ). Therefore, it is speculated that genetic differences may also contribute to the differing rates of distant metastasis in MBC versus FBC.…”

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era

“…Studying the molecular differences between the FBC and MBC methylomes, Abeni et al (2021) reported different DNA methylation levels of GTPase-related genes (RHO-GAP, RHO-GEF, and RAB GTPase) and keratin-related genes as an essential component of the cytoskeleton rearrangement biological process [119]. Known as key regulators of the cytoskeleton architecture, RHO GTPases are involved in membrane trafficking, gene transcription, cell migration, invasion, adhesion, survival and growth, and cancer initiation, metastasis and therapeutic responses [120].…”