Molecular pathogenesis of endometrial and ovarian cancer

Abstract

Pregnancy, breastfeeding, and oral contraceptive pill use interrupt menstrual cycles and reduce endometrial and ovarian cancer risk. This suggests the importance of turnover within Mullerian tissues, where the accumulation of mutations in p53 and PTEN has been correlated with number of cycles. The most common type of endometrial cancer (Type I) is endometrioid and molecular abnormalities include mutations in PTEN, KRAS and β-catenin. The Type I precursor is Endometrial Intraepithelial Neoplasia which displays PTEN defects. Type II endometrial cancer (whose precursors are less clear) includes serous and clear cell tumors and the most common alteration is p53 mutation. For ovarian cancer, histopathologic types parallel endometrial cancer and include serous, mucinous, endometrioid, and clear cell; some molecular features are also shared. The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 "signature". Mutations in KRAS, BRAF and PTEN are described in mucinous, endometrioid and low grade serous cancers and these may originate from ovarian cortical inclusion cysts. A consideration of molecular and other pathogenetic features, like epidemiology and histopathology, may provide a better understanding of endometrial and ovarian cancer.

Figure 1

Age-Specific Incidence Rates of Endometrial and Ovarian Cancers¹. ¹Age-Specific Cancer Incidence Rates are per 100,000 and are age-adjusted to the 2000 US Standard Population. Rates include all races and pertain to invasive cancers only. Adapted from Ries et al. [199] http://seer.cancer.gov/csr/1975_2005/.

Figure 2. Multiple Pathways to Endometrial Carcinoma

Inactivation of PTEN occurs early in Type I endometrial carcinomas, prior to any detectable histologic change (“latent precancer”). Non-genetic hormonal selection factors, such as increased estrogen unopposed by progesterone, may modulate cancer risk through their actions on preclinical latent precencers, which may undergo involution or expansion with additional mutation. Further mutations, sometimes accelerated by a microsatellite instability phenotype (MI), define stepwise progression events to EIN and then adenocarcinoma. Serous (Type II) tumors are initially observed as short-lived preinvasive precursors designated as serous intraepithelial carcinoma (EIC). Endometrial glandular dysplasia (EGD) is a newly described lesion with p53 inactivation and a histology that is intermediate between normal and serous EIC. Progression and involution rates of EGO lesions over time are unknown and it remains to be determined how often EGD lesions are actual precursors of Type II cancers. Rarely, individual examples of Type I tumors may acquire an early or late p53 inactivation event, causing a hybrid or heterogeneous tumor, respectively [adapted from reference 43]

Figure 3. Relationship between Potential Precursor Lesions and Histologic Types of Ovarian Cancer

Three pathways for ovarian cancer are proposed: Pathway 1 begins in the ovary in a majority of cases within Mullerian inclusion cysts (MICs). MICs may form when the ovarian surface or other epithelium (such as salpingeal) becomes entrapped after ovulation or by surface adhesion. MICs have been the classic explanation for the origin of benign serous and mucinous cystadenomas, some of which may progress through borderline counterparts, serous borderline or mucinous borderline, into carcinomas. Pathway I may apply to some low grade invasive serous carcinomas. Pathway II describes the origin of endometrioid and clear cell carcinoma from endometriosis derived from transpo1t and implantation of endometrial cells from the uterus. Counterparts of each type may occur in the uterine lining. Pathway III involves the origin of metastatic (high grade) serous carcinomas and is best characterized in the distal fallopian tube [adapted from 128].