Precursors Of Ovarian Carcinoma Research Articles

High grade serous ovarian carcinomas originate in the fallopian tube

High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.

Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer

Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. Conditional suppression of functional p53 increased p110alpha transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by gamma-irradiation both diminished p110alpha protein levels in normal OSE and ovarian cancer cells. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer.

Evaluation of normal-sized ovaries associated with primary peritoneal serous carcinoma for possible precursors of ovarian serous carcinoma

Objective Three groups of “high-risk” ovaries have previously been studied for possible precursors of ovarian carcinoma: ovaries removed prophylactically from women at high risk, normal ovaries contralateral to a unilateral ovarian carcinoma, and normal ovarian tissue found adjacent to primary ovarian carcinomas. No data are available for a fourth high-risk group: normal-sized ovaries from women with primary peritoneal serous carcinoma. Methods Grossly normal-sized ovaries from 26 patients with primary peritoneal serous carcinoma were compared to normal-sized ovaries from 75 controls. Controls were divided at the median age for age matching. Cortical inclusions, surface epithelial invaginations (clefts), surface papillary proliferation, and calcifications were examined. Results Case versus control comparisons showed, respectively, inclusions in 92% and 68% of patients, clefts in 54% and 59%, and papillomatosis in 35% and 16%. For each profile of ovary on one section, cases versus controls, respectively, had a mean number of inclusions of 5.55 and 3.97, size of the largest inclusion of 1.28 and 1.27 mm, and depth of the deepest cleft of 1.04 and 0.9 mm. After controlling for age, correcting for multiple comparisons and using two-sided chi square, there were no significant differences between cases and controls in all the parameters measured. In comparing the two control groups, the only significant finding was that the young group displayed deeper clefts than the older group (2.06 versus 0.9 mm, respectively). Conclusion Grossly normal-sized ovaries from women with primary peritoneal serous carcinoma display no significant differences in inclusions, clefts, papillomatosis, and calcifications in comparison to age-matched controls.

Numerical abnormalities of chromosomes 1, 11, 17, and X are associated with stromal invasion in serous and mucinous epithelial ovarian tumours.

The clinical behaviour of ovarian tumours of low malignant potential (LMP) is unpredictable and it has been suggested that the majority of these lesions have no invasive potential. This study has analysed 92 epithelial ovarian tumours [11 mucinous cystadenomas, 18 mucinous LMP tumours, 15 mucinous carcinomas (9 FIGO stage I), 16 serous cystadenomas, 15 serous LMP tumours, and 17 serous carcinomas (11 FIGO stage I)] for numerical abnormalities of chromosomes 1, 11, 17, and X by interphase cytogenetics. Overall, numerical aberrations were identified in none of the cystadenomas, 15 per cent of serous LMP tumours, 17 per cent of mucinous LMP tumours, 67 per cent of mucinous carcinomas, and 82 per cent of invasive serous carcinomas. In mucinous LMP tumours, chromosome gains were associated with spindled nuclear morphology. Chromosome abnormalities were significantly more frequent in invasive mucinous (overall p< 0.01; stage I p< 0.05) and serous (overall p< 0.001; stage I p< 0.01) carcinomas than in the corresponding LMP tumours. No significant relationship between either stromal invasion or tumour type and the pattern of chromosome loss or gain was identified, although monosomy X was identified almost exclusively in invasive serous carcinomas. These observations are consistent with the concept that LMP tumours are unlikely to be precursors of ovarian carcinoma, but suggest that chromosome instability is important in the development of the invasive phenotype.