The tubal fimbria is a common site of origin for early (tubal intraepithelial carcinoma or TIC) serous carcinomas in women with familial BRCA1 or 2 mutations (BRCA+). Somatic p53 tumour suppressor gene mutations in these tumours 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 tubal mucosa from BRCA+ women. To examine the relationship between p53 signatures and TIC, 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 equally common in non-neoplastic tubes from BRCA+ women and controls, but more frequently present (53%) and multifocal (67%) in fallopian tubes also containing TIC. Like prior studies of TIC, p53 signatures predominated in the fimbriae (80-100%) and targeted secretory cells (HMFG2 + /p73-), with evidence of DNA damage by co-localization of gamma-H2AX. Laser-capture microdissected and polymerase chain reaction-amplified DNA revealed reproducible p53 mutations in eight of 14 fully-analysed p53 signatures and all of the 12 TICs; TICs and their associated ovarian carcinomas shared identical mutations. In one case, a contiguous p53 signature and TIC shared the same mutation. Morphological intermediates between the two, with p53 mutations and moderate proliferative activity, were also seen. This is the first report of an early and distinct alteration in non-neoplastic upper genital tract mucosa that fulfils many requirements for a precursor to pelvic serous cancer. The p53 signature and its malignant counterpart (TIC) underline 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.

In this recent paper, the frequency of p53 signatures in the fallopian tubes of BRCA + women was recorded as 24% (10/24), in contrast to women with other disorders, which was 33% (19/58). We have since discovered that a proportion of the cases originally classified as BRCA + in our high-risk population had not been documented genetically as having a BRCA mutation. To address this error, we reviewed p53 immunostains from 605 tissue blocks of 75 consecutive prophylactic salpingectomies from women with documented BRCA mutations at our institution. This cohort included the cases in our report; 37% (28/75) contained p53 signatures. This does not alter the conclusion that p53 signatures have a similar frequency in women with and without a documented BRCA mutation. However, it provides a more accurate estimate of the latter and reiterates the hypothesis that the initial phase of serous carcinogenesis in the fallopian tube is not BRCA-dependent.