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Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women
C Szych1, A Staebler, D C Connolly
1Departments of Pathology* and Gynecology and Obstetrics,dagger The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by mucinous ascites and multifocal peritoneal mucinous tumors. Women with PMP often have mucinous tumors involving both the appendix and the ovaries. Several previous histopathological and immunohistochemical studies of PMP have suggested that most, if not all, cases of PMP in women are derived from mucinous adenomas of the appendix rather than from primary ovarian tumors. A few studies of the molecular genetics of PMP have been recently reported. However, these studies analyzed only a small number of cases and some included a heterogeneous group of mucinous tumors, including both benign and malignant appendiceal and ovarian tumors. We analyzed K-ras mutations and allelic losses of chromosomes 18q, 17p, 5q, and 6q in a substantial number of morphologically uniform cases of PMP with synchronous ovarian and appendiceal tumors as well as in appendiceal mucinous adenomas (MAs) and ovarian mucinous tumors of low malignant potential (MLMPs) unassociated with PMP. Each of the 16 PMP cases (100%) analyzed demonstrated identical K-ras mutations in the appendiceal adenoma and corresponding synchronous ovarian tumor. K-ras mutations were identified in 11 of 16 (69%) appendiceal MAs unassociated with PMP and in 12 of 16 (75%) ovarian MLMPs unassociated with PMP. Two PMP cases showed identical allelic losses in the matched ovarian and appendiceal tumors. A discordant pattern of allelic loss between the ovarian and appendiceal tumors at one or two of the loci tested was observed in six PMP cases. In all but one instance, LOH was observed in the ovarian tumor, whereas both alleles were retained in the matched appendiceal lesion, suggesting tumor progression in a secondary (metastatic) site. Our findings strongly support the conclusion that mucinous tumors involving the appendix and ovaries in women with PMP are clonal and derived from a single site, most likely the appendix.
Insights
Pseudomyxoma peritonei (PMP) in women likely originates from the appendix. Genetic analysis shows identical K-ras mutations in appendiceal and ovarian tumors, supporting a single-site origin for PMP.
Area of Science:
- Oncology
- Gastroenterology
- Genetics
Background:
- Pseudomyxoma peritonei (PMP) is a rare condition causing mucinous ascites and peritoneal tumors.
- PMP in women often involves both the appendix and ovaries, with debated origins.
- Previous studies suggest appendiceal origin but lacked comprehensive molecular data.
Purpose of the Study:
- To investigate the clonal origin of PMP in women using molecular genetic markers.
- To analyze K-ras mutations and chromosomal allelic losses in PMP, appendiceal adenomas, and ovarian tumors.
- To determine if PMP arises from a single primary site, likely the appendix.
Main Methods:
- Analyzed K-ras mutations and allelic losses (18q, 17p, 5q, 6q) in 16 PMP cases with synchronous ovarian and appendiceal tumors.
- Compared genetic profiles of PMP tumors with non-PMP appendiceal mucinous adenomas (MAs) and ovarian mucinous tumors of low malignant potential (MLMPs).
- Utilized histopathological and immunohistochemical data for case selection.
Main Results:
- All 16 PMP cases (100%) showed identical K-ras mutations in both appendiceal and ovarian tumors.
- K-ras mutations were found in 69% of appendiceal MAs and 75% of ovarian MLMPs.
- Discordant allelic loss patterns suggested tumor progression in secondary sites, with ovarian tumors often showing loss while appendiceal lesions retained alleles.
Conclusions:
- Findings strongly support a clonal origin for PMP, with tumors in the appendix and ovaries derived from a single primary site.
- The appendix is the most probable primary site for PMP in women.
- Molecular genetic analysis provides critical insights into PMP pathogenesis.