The molecular pathogenesis of hereditary ovarian carcinoma

Abstract

BACKGROUND: BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas. METHODS: Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (!10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms. RESULTS: Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P ¼ .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P ¼ .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P ¼ .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P ¼ .002). CONCLUSIONS: The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion. Cancer 2010;116:5261-71.

A cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA mutation carriers

“…All of the women in our control group underwent RRSO because of a family history of ovarian cancer or personal history of breast cancer; all had normal pre-operative CA 125 and ultrasound. Also, unlike the control group in other studies, our control group of patients had genetic testing and no BRCA mutations were detected [9,13,19,21].…”

“…In a smaller cohort of 75 BRCA mutation carriers, Saleemuddin et al correlated p53 signatures in fallopian tubes removed at RRSO with less robust risk factors for ovarian cancer and found a relationship between older age at first birth and lower parity and p53 signatures [27]. The relatively high frequency of p53 overexpression in tubal epithelium among BRCA mutation carriers and controls suggests that alterations in genes other than or in addition to p53 are needed to promote neoplastic transformation in the fallopian tube [13,18,19,26]. Norquist et al showed that foci of p53 overexpression in BRCA1 mutation carriers had decreased p27 expression compared to BRCA2 and control patients and suggested a possible role for cyclin-dependent kinase inhibitor 1B (CDKN1B) (which encodes p27) in BRCA1 tubal carcinogenesis.…”

“…When they limited their analysis to p53 foci in histologically normal fallopian tubes removed from BRCA1/2 mutation carriers at RRSO, they found no evidence of loss of heterozygosity of the wild type allele. The authors concluded that additional alterations are required within p53 overexpressing epithelium for malignant transformation to occur in the fallopian tube of high-risk BRCA mutation carriers [19]. Others have suggested that genetic dysregulation of additional genes (such as p27, PTEN, PAX2, WT-1 and/or p16) may be important early events in the development of serous carcinoma [1,16,19,20].…”

“…The p53 signature, defined as a consecutive series of a variable number of nuclei, that stain positively for p53 by immunohistochemistry, has been postulated to be a precursor of STIC and ultimately, invasive serous carcinoma by some workers [9,13]. However, the number of p53 positive nuclei necessary to alter cellular function and the biologic significance of other lesions such as atypia/low grade dysplasia and tubal hyperplasia are unknown [18][19][20]. The significance of focal p53 overexpression or isolated p53 signatures that are frequently observed in histologically normal tubal epithelium, independent of BRCA mutation, also remains unclear [13].…”

Progesterone action in breast, uterine, and ovarian cancers

“…hormone producing) cells (Chodankar, et al 2005; Hong, et al 2010; Yen, et al 2012) and in humans with either a BRCA1 or BRCA2 mutation (Widschwendter, et al 2013) demonstrated that BRCA mutations confers higher serum (circulating) levels of both estrogen and progesterone. Moreover, serous tubal intra-epithelial carcinoma in the distal end of the fallopian tube was discovered in 10-15% of BRCA carriers who had prophylactic salpingo-oophorectomy (Folkins, et al 2008; Norquist, et al 2010). Ultimately, little mechanistic information exists related to the impact that hormones have on the prevention and/or pathogenesis of ovarian cancer.…”