Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

Abstract

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas', which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies.

Methylation and ovarian cancer: Can DNA methylation be of diagnostic use? (Review)

“…If it was possible to identify OC using a standard cytological test from the cervix, a screening program for OC could be included in the existing screening program for cervical cancer. Methylation changes in fimbrial cells, which can identify ovarian carcinomas, have already been described (102). Likewise, it has also been possible to identify an association between methylation of PolyComb group target genes HOXA9 and HOXA11 in normal endometrium and the presence of OC (79).…”

Serous tubal intraepithelial carcinomas associated with high‐grade serous ovarian carcinomas: a systematic review

“…This highlights the need for additional complementary strategies for effective prevention of HGSOCs. Recent work has identified promising biomarkers that may become useful in this regard …”

The secondary laticifer differentiation in rubber tree is induced by trichostatin A, an inhibitor of histone acetylation

“…Therefore, tumor is considered to be a kind of cellular epigenetic disease [18][19][20] . Such histone deacetylation inhibitors as O-benzylhydroxylamine Fig.…”

“…The dynamic changes in deacetylation and acetylation of histones are modulated by histone deacetylase (HDA) and histone acetyltransferase [28] . By modulating the histone acetylation or directly interacting with target proteins, the HDAs have pleiotropic effects on regulating plant growth and development [16][17][18][19] , abiotic stress responses [18,20,26] and photomorphogenesis [24] . The TSAinduced secondary laticifer differentiation suggests that HDA(s) may negatively regulate the jasmonate signaling.…”