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Ovarian serous tumors (molecular pathology)

Wednesday 10 September 2014

Types

- ovarian epithelial ovarian cancer (EOC)
- ovarian serous borderline tumor (SBT)
- ovarian atypical proliferative serous tumor (APST)
- ovarian micropapillary serous carcinoma (MPSC) or “non-invasive low-grade serous carcinoma”
- ovarian low-grade serous carcinoma (OLGSC)
- ovarian high-grade serous carcinoma (OHGSC)

The relationship of APST and MPSC to LGSC based on morphologic studies was supported by mutational analysis, gene expression studies and methylation profiling demonstrating that these three tumor types shared molecular alterations that differed dramatically from HGSC.

Initial molecular genetic studie focused on individual genes but more recent studies have highlighted the importance of molecular signaling pathways).

For example, the MAPK signaling pathway is important for the cellular response to a variety of growth and differentiation factors and activating mutations in KRAS or one of its downstream effectors, BRAF, (mutations of KRAS and BRAF are mutually exclusive) results in constitutive activation of MAPK-mediated signaling in more than half of APSTs, MPSCs and LGSCs.

In addition, a 12-bp insertion mutation of ERBB2 (encoding HER2/neu), which activates an upstream regulator of K-Ras, has been detected in 9% of these tumors. Interestingly, tumors with ERBB2 mutations lack KRAS and BRAF mutations.

Accordingly, 60-70% of APSTs, MPSCs and LGSCs express active MAPK; they rarely harbor TP53 mutations.

Recent studies have further clarified the molecular pathogenesis of APST, MPSC and LGSC.

First, KRAS and BRAF mutations have not been detected in serous cystadenomas, the putative precursor of SBTs, but laser capture microdissection studies have detected these mutations in the adenoma epithelium and APST epithelium in serous cystadenomas containing small APSTs suggesting that these mutations occur early in the development of APST.

In an attempt to elucidate the relationship of APST to LGSC a recent study compared the gene expression profiles of APST, MPSC and LGSC and found that MPSC is closer molecularly to invasive LGSC than to APST and that the genes involved in MAPK signaling showed higher expression in MPSC than in APST.

In addition, a previous study reporting that MPSC harbors a pattern of chromosomal imbalance distinct from that of APST confirms the proposal that LGSC develops in a stepwise fashion from cystadeno(fibro)ma to APST and MPSC, supporting the biological role of the KRAS-BRAF-MEK-MAPK pathway in the development of LGSC.

By globally profiling the epigenetic landscape, it has been recently reported that the methylation profiles in low-grade serous carcinoma are closer to APST and serous cystadenoma than high-grade serous carcinoma. This finding lends further support to the dualistic model of ovarian serous carcinogenesis.

In contrast to LGSC, HGSC harbors TP53 mutations in >95% of cases, but rarely contains KRAS or BRAF mutations.

Aside from TP53 mutations no other mutations are consistently found in sporadic (non-familial) HGSCs including mutations of BRCA1 and BRCA2, which characterize familial HGSC (The Cancer Genome Atlas, unpublished).

On the other hand, inactivation of the BRCA1/2 genes by other mechanisms, such as hypermethylation of the BRCA1 promoter, occurs relatively frequently and as a result inactivation of BRCA1/2 by mutation or other mechanisms occurs in 40-50% of sporadic HGSCs.

The most striking molecular feature of HGSC is diffuse and high levels of DNA copy number gains or losses, which include CCNE1 (cyclin E1), NOTCH3, AKT2, RSF1, and PIK3CA loci.

Despite their distinct molecular signatures, LGSC and even an APST is sometimes clonally associated with a synchronous HGSC, suggesting that such progression rarely does occur.

Credits

- Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Kurman RJ, Shih IeM. Hum Pathol. 2011 Jul;42(7):918-31. doi : 10.1016/j.humpath.2011.03.003 PMID: 21683865 (Free)