Monday 23 August 2004
JRC:8985 : Ovarian serous cystadenocarcinoma.
Definition: Ovarian carcinoma is the leading cause of death from gynecologic cancer and one of the most frequent causes of fatal malignancy in women. The poor prognosis is likely related to the degree of peritoneal dissemination associated with ascites accumulation.
Approximately 25,000 ovarian cancers are diagnosed in the U.S. annually. 75% of cases diagnosed in the advanced stage when they are largely incurable. Ovarian cancer is the most lethal gynecologic malignancy.
Epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features.
- Type 1
One group of tumors, designated type I, is composed of :
low-grade serous carcinoma,
low-grade endometrioid carcinoma,
clear cell carcinoma,
transitional (Brenner) carcinoma.
These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable.
They lack mutations of TP53, but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm, often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression.
- Type 2
In contrast, another group of tumors, designated type II, is highly aggressive, evolves rapidly and almost always presents in advanced stage.
Type II tumors include:
conventional high-grade serous carcinoma,
malignant mixed mesodermal tumors (carcinosarcoma).
They display TP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors.
What have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube.
Endometrioid and clear cell tumors have been associated with endometriosis that is regarded as the precursor of these tumors. As it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation, it is reasonable to assume that the endometrium is the source of these ovarian neoplasms.
Finally, preliminary data suggest that mucinous and transitional (Brenner tumor) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia.
- 9p22 (BNC2)
- 19p13 (20852633)
two loci approaching genome-wide significance at 3q25 and 17q21
- Opioid binding protein cell adhesion molecule (OPCML) is frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo.
- OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4.
- OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition.
- Exogenous recombinant OPCML domain 1–3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism.
Common variants at 19p13 are associated with susceptibility to ovarian cancer. Bolton KL, Tyrer J, Song H, Ramus SJ et al. Nat Genet. 2010 Sep 19. PMID: 20852633
A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Goode EL, Chenevix-Trench G, Song H, Ramus SJ et al. Nat Genet. 2010 Sep 19. PMID: 20852632
The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory. Kurman RJ, Shih IM. Am J Surg Pathol. 2010 Feb 11. PMID: 20154587