A multi‐step model of pelvic serous carcinogenesis that originates in the distal fallopian tube from a novel precursor lesion.

The fimbria is a preferred site for tubal intraepithelial serous carcinoma (TIC) in BRCA+ women. TICs often co‐exist with pelvic serous carcinomas and exhibit somatic p53 gene mutations. We recently described strong p53 immunostaining ‐ “p53 signatures” ‐ in benign tubal mucosa. We correlated p53 signatures with BRCA status, location, cell type, tubal inflammation, DNA damage, p53 mutation status and coexisting TIC. P53 signatures were common in tubes from BRCA+ women and controls (24 and 33%), and more frequentl (53%) and multi‐focal (67%) in tubes with TIC. Like TICs, p53 signatures predominated in secretory cells(HMFG2+/p73‐)in the fimbria rather than ovarian surface epithelial cels. p53 signatures were γ‐H2AX(+), suggesting unrepaired DNA damage, but were not increased in chronic salpingitis. eight of 14 p53 signatures were p53 mutation(+); transitions from p53 signature to TIC were documented. The p53 signature is a novel, compelling candidate precursor to pelvic serous carcinoma, emerging independent of BRCA status and much more prevalent in the fimbria than the ovarian surface epithelium. It is an integral component of a pathobiologic continuum; initiating with un‐repaired DNA damage, terminating in ovarian or pelvic serous carcinoma, and sharing sequence specific mutations in p53. Its fimbrial location is consistent with an ovulation‐mediated genotoxic insult to a vulnerable target cell (secretory) population.