A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations

Abstract

Background: Early serous carcinomas predominate in the fimbria of women with BRCA mutations (BRCA+). An entity in non-neoplastic mucosa sharing several properties of early serous carcinomas--the "p53 signature"--has been described in the distal fallopian tube and proposed as a precursor to serous carcinomas. This study compared the prevalence of p53 signatures in ovarian cortical inclusion cysts (CICs) and fallopian tubes from BRCA+ women and explored their relationship.

Design: All tissues from 75 completely excised ovaries and tubes obtained during prophylactic surgery were studied by conventional microscopy, immunostaining for p53, and in selected cases, gamma-H2AX (DNA damage). P53 signatures were defined as 12 or more consecutive p53-positive secretory cell nuclei. Their prevalence in fallopian tubes and CICs was recorded, compared to an existing database of consecutive women without a suspicion of BRCA+ or ovarian cancer, and correlated with the number of CICs.

Results: Tubal p53 signatures were detected in 29 of 75 cases (38%); 20 of 30 (66%) signatures examined were gamma-H2AX-positive. One ovary contained a small gamma-H2AX negative p53 signature on the ovarian surface; no p53 signatures were identified in CICs. The prevalence of BRCA+ p53 tubal signatures was similar to that of women with unknown BRCA status (38 v 33%). Presence of p53 signatures did not correlate with number of CICs.

Conclusions: p53 signatures were common in the fallopian tubes of BRCA+ women, were not identified in CICs, and did not correlate with the latter. The tubal p53 signature merits serious consideration as an important early event in serous carcinogenesis in BRCA+ women.

Figure 1

Benign-appearing salpingeal epithelium (A&C) with strong nuclear staining for p53 (p53 signatures, B&D). Interrupted staining is due to the co-existing non-staining ciliated cells (B) in contrast to continuous staining (D) in a homogeneous population of secretory cells.

Figure 2

Graphic depiction (from left to right) of the distribution of p53 signatures in tubes from BRCA+ women, consecutive women untested for BRCA or negative for ovarian cancer from a prior study (right),, BRCA+ OSE, and BRCA+ ovarian CICs.

Figure 3

Correlation of p53 signatures and ã-H2AX staining, a marker for DNA damage. Hematoxylin and eosin stained tube (A, D) and ovary (G), and respective p53 immunostaining (B, E, and H) and localization of ã-H2AX (C, F, and I). Note the lack of γ-H2AX localization in the ovary (I).