Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, remove or prevent the earliest stages of the most lethal form of ovarian cancer. The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the ‘p53 signature’, suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa. A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of ‘fimbrial-ovarian’ serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.

Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic. Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404–21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.

Purpose: A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. Patients and Methods: Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. Result: Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. Conclusion: The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.

Ovarian epithelial cancer is diagnosed in approximately 25,000 women yearly in the United States, accounting for approximately 12,500 deaths. Of these tumors, serous cancer is the most lethal, due to its capacity to spread beyond the reproductive tract and involve the peritoneal surfaces or distant organs. Conventional classification systems designate tumor origins principally on the location of the largest tumor. However, despite the fact that the largest tumors typically involve the ovaries, demonstrations of a precise starting point for these tumors, including precursor lesions, have been inconsistent. In recent years, a major effort to prevent serous cancer in genetically susceptible women with mutations in BRCA1 or BRCA2 has spawned the practice of prophylactic salpingo-oophorectomy. This practice has surprisingly revealed that many early cancers in these women arise in the fallopian tube, and further studies have pinpointed the distal (fimbrial) portion as the most common site of origin. Emerging studies that carefully examine the fallopian tubes suggest a high frequency of early cancer in the fimbria in unselected women with ovarian and peritoneal serous carcinoma, raising the distinct possibility that a significant proportion of these tumors have a fimbrial origin. The evidence for these discoveries and their relevance to serous cancer classification, early detection and prevention are addressed in this review. A model for pelvic serous cancer is proposed that takes into account five distinct variables which ultimately impact on origin and tumor distribution: (1) location of target epithelium, (2) genotoxic stress, (3) type of epithelium, (4) mitigating genetic factors, and (5) tumor spread pattern. Ultimately, this model illustrates the importance of identifying cancer precursors, inasmuch as these entities are useful as both surrogate endpoints for their respective malignancies in epidemiologic studies and natural targets for cancer prevention.