Evidence supporting a multi-step model of pelvic serous carcinogenesis that originates in the distal fallopian tube.

B223

The tubal fimbria is a common site of origin for early tubal serous carcinomas in women with familial BRCA1 or 2 mutations (BRCA+). Moreover, these early tubal carcinomas commonly co-exist with tumors otherwise classified as ovarian or peritoneal serous cancers. Somatic p53 tumor suppressor gene mutations in these tumors suggest a pathogenesis involving DNA damage, p53 mutation and progressive loss of cell cycle control. We recently identified foci of strong p53 immunostaining - termed "p53 signatures" - in benign-appearing tubal mucosa from BRCA+ women. To address the relationship between p53 signatures and early tubal carcinoma, we compared location (fimbria vs ampulla), cell type (ciliated vs. secretory), evidence of DNA damage and p53 mutation status between the two entities. P53 signatures were common in non-neoplastic tubes from BRCA+ women and controls (24 and 33%), but were more frequently present (53%) and multifocal (67%) in fallopian tubes also containing early tubal carcinoma. Similar to early tubal carcinomas, p53 signatures predominated in the fimbriae (80-100%) and targeted secretory cells (HMFG2+/p73-), with evidence of DNA damage by co-localization of γ-H2AX. Laser-capture micro-dissected and PCR-amplified DNA revealed reproducible p53 mutations in 8 of 14 fully-analyzed p53 signatures and all of 12 early tubal carcinomas; 10 of 10 early tubal carcinomas and their associated ovarian or pelvic serous carcinomas shared identical p53 mutations. In one case, a p53 signature merged with an intraepithelial carcinoma and shared the same p53 mutation. This is the first report of an early and visually quantifiable alteration in non-neoplasatic upper genital tract mucos that fulfills many requirements for a precursor to pelvic serous cancer and is independent of BRCA status. The tubal p53 signature and its malignant counterpart underscore the significance of the fimbria, both as a candidate site for serous carcinogenesis and as a target for future research on the early detection and prevention of this disease.