Estrogen receptor-positive, BRCA1-deficient breast cancer: BRCA1-epimutated tumors presenting a piece to the puzzle

While the majority of breast cancers arising in women with germline BRCA1 pathogenic variants (gBRCA1) are triple-negative (TNBC), these women also have a moderately increased risk of ER+ breast cancers. The contribution of BRCA1 deficiency to the development of ER+ breast cancers in gBRCA1 carriers is incompletely understood. BRCA1 epimutations (promoter hypermethylation) have emerged as a major factor in TNBC. About 25–30% of all TNBCs harbor clonal BRCA1 epimutations. In the majority of these patients, the tumor seems to arise from small subclones of normal cells harboring constitutional BRCA1 epimutations. Mirroring findings for gBRCA1 carriers, a minor fraction of ER+ breast cancers seems to arise from BRCA1 epimutated subclones as well. An important difference between normal cells in individuals harboring gBRCA1 pathogenic variants and BRCA1 constitutional epimutations is that constitutional epimutations are mosaic, most often affecting < 1% of an individual’s cells. Considering cancers arising in gBRCA1 carriers, where all cells of the individual are affected, in some cases BRCA1 deficiency may be of limited importance to the tumorigenesis; the BRCA1 variants could be passenger events only. In contrast, the fact that women harboring constitutional epimutations in a small fraction of normal cells have increased risk of developing a TNBC harboring fully clonal BRCA1 epimutations strongly suggest BRCA1 deficiency to be an underlying cause in the tumor evolution. Most likely, the same argument applies to ER+ tumors harboring clonal BRCA1 epimutations, making these cancers valuable tools exploring the role of BRCA1 deficiency in development of ER+ breast cancers.