title: Pathogenesis of serous, extra-uterine Müllerian epithelial cancer and therapeutic implications.
abstract: Serous extra-uterine Müllerian tumors include lesions previously classified either as serous ovarian, fimbrial, or primary peritoneal tumors. They should be distinguished from intra-uterine (endometrial) serous tumors in spite of their common Müllerian differentiation lineage due to distinctive clinical-pathological parameters. Increased risk for these cancers is driven primarily by cell non-autonomous hormonal factors associated with menstrual cycle progression, which can be accentuated by mutations inBRCA1/2. Additional factors, such as inflammatory conditions and others, may also contribute to elevated cancer risk in some individuals. The most consistent molecular alterations associated with serous extra-uterine Müllerian carcinomas, whether they arise in the context of familial predisposition orBRCA-independent hormonal factors, include severe aneuploidy superimposed on P53 mutations. Their near polyploid nature strongly suggests a role for mitotic errors associated with cytokinesis failure in their pathogenesis. A molecular mechanism is proposed involving a combination of both cell non-autonomous and cell autonomous factors in the development and progression of serous extra-uterine Müllerian tumors. Cell non-autonomous factors lead to increased cellular proliferation in extra-uterine serous Müllerian epithelium and contribute to the site-specificity of cancers associated with germlineBRCAmutations. Cell autonomous factors in individuals withBRCA1mutations lead to failure of cytokinesis following recovery from a cell cycle arrest at the mitotic spindle assembly checkpoint. In individuals with intactBRCA1/2function, recovery from such arrest might be facilitated byCCNE1amplification and ensuing centrosome duplication leading to increased microtubule anchoring, accounting for frequent amplification of this cyclin observed in tumors not associated withBRCA1/2mutations. The cell non-autonomous factors provide an opportunity for using pharmacological means to control cancer incidence in individuals at elevated risk for these cancers such asBRCA1/2mutation carriers, underscoring the importance of better understanding their determinants and downstream targets. The cell autonomous factors discussed here account for the molecular features of high-grade serous extra-uterine Müllerian carcinomas, which are regarded as a disease of chromosomes, and underscore the potential merit of targeting components of the spindle assembly checkpoint in their clinical management.
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
keywords: BRCA1; Ovarian carcinoma; aneuploidy; cell non-autonomous mechanism