Bringing the p53 signature into focus

The origin of ovarian cancer, and specifically high-grade serous carcinoma, has been the subject of considerable debate over the past 25 years, and the elucidation of this issue has been hampered because >90% of these tumors are discovered after considerable tumor growth has occurred, obscuring not only the ovaries but also the fallopian tubes and peritoneal surfaces. This propensity for discovering high-grade serous carcinomas at a late stage has not been altered appreciably by conventional approaches to early detection, and the beneficial role of serologic screening for cancer-related biomarkers remains to be proven. Thus, identifying the precursors to ovarian malignancies and their relevance to the detection or prevention of ovarian cancer has been a major objective in ovarian cancer research. At least a partial answer to the question of tumor origin has come from the study of women who harbor an inherited mutation in either the BRCA1 or BRCA2 breast cancer gene (BRCA-positive). The inheritance of a heterozygous loss of function mutation of BRCA1 or BRCA2 gives rise to an average 10-fold increased risk of developing ovarian cancer. Eight percent of BRCA-positive women who undergo risk-reducing surgery will have an early serous (and, less commonly, endometrioid) carcinoma identified. The accumulated studies in the past decade increasingly have implicated the distal fallopian tube rather than the ovary as the source of disease in these women, and approximately 80% of these early cancers are traced to an early (intraepithelial) carcinoma in the fimbrial mucosa. This same intraepithelial carcinoma also can be identified in up to 47% of presumed sporadic ovarian and primary peritoneal serous cancers, suggesting that the salpingeal mucosa is prone to malignancy in all women, albeit more exquisitely in the BRCA-positive population, which is handicapped by the germline mutation in 1 functioning allele. It is noteworthy that 1 previous report suggested a 120-fold greater risk of fallopian tube cancer in BRCA1mutation carriers. Inactivating p53 mutations are identified in virtually all serous carcinomas and most often lead to the accumulation of altered protein product in the tumor cell nuclei. In a previous study of benign tubal mucosa from BRCA-positive women, investigators observed an increase in epithelial atypia and p53 positivity; and, recently, a candidate serous cancer precursor—the p53 signature—was described. Like its malignant counterpart, the p53 signature was observed most commonly in the fimbria, harbored evidence of DNA damage, increased p53 staining and p53 mutations, involved the tubal secretory cell, was observed in continuity with malignancy, and was present more commonly in women who had serous carcinoma. Significantly, the p53 signature was nearly equally common in BRCA-positive women and population controls; thus, it was proposed as a generic precursor that was independent of BRCA status. On the basis of the high frequency of BRCA1 or BRCA2 gene inactivation in familial and sporadic ovarian cancer, it was presumed that loss of heterozygosity (LOH) or other functional loss of the remaining BRCA1 or BRCA2 allele was an important rate-limiting event in the transition from p53 signature, to serous tubal intraepithelial carcinoma, and, finally, to serous carcinoma. In this issue of Cancer, Norquist et al have brought the p53 signature (or, as they call it, p53 foci) into a clearer focus, albeit with some controversy. These authors from the University of Washington School of Medicine make at least 3 important observations, including 1) that p53 signatures are more common in BRCA-positive women, 2) that the index of tubal epithelial proliferation is higher in the BRCA-positive group, and 3) that the transition from p53 signature to intraepithelial carcinoma is marked by a loss of function of the remaining BRCA allele. The latter observation is the first to