Impact of BRCA mutations, age, and hormone status on the molecular phenotype of the human Fallopian tube

The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous ovarian cancer (HGSOC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying BRCA1/2 mutations. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity, shedding new light into the prevention and/or early detection of tumorigenesis in these women. Covariates such as surgical indications can confound BRCA1/2-related differences reported in the literature.We systematically document and highlight the degree of variations across normal human FT, defining five FT groups capturing major cellular and molecular changes across various reproductive stages and associate these with various clinical covariates but not heterozygous BRCA1/2 mutation status.