Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas.

Abstract

Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin. In this work, we characterize the gynecological tumors of female patients with Mulibrey nanism in detail. In addition to tumors of the fibrothecoma group, 18% (4/22) of the patients were observed with epithelial neoplasias, including 2 ovarian adenofibromas, 1 ovarian poorly differentiated adenocarcinoma and 1 endometrial adenocarcinoma. To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. No mutations in the open-reading frame of TRIM37 were detected. Two alternatively spliced variants were found, one lacking exon 23 and one exon 2. TRIM37del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37del2:TRIM37 ratio was increased. In normal ovary, TRIM37 was localized in the cytoplasm of stromal cells, especially theca cells surrounding developing follicles. TRIM37 transcript was found in all sporadic fibrothecomas examined, but 80% (20/25) of the tumors showed reduced or absent expression of TRIM37 protein. Allelic loss at the TRIM37 locus (17q22-23) was observed in 6% of sporadic fibrothecomas. Nearly half of the sporadic fibrothecomas showed evidence of CpG promoter methylation, suggesting promoter downregulation as one mechanism of reduced TRIM37 expression. In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas.

• Authors: Susann Karlberg, Marita Lipsanen-Nyman, Heini Lassus, Jukka Kallijärvi, Anna-Elina Lehesjoki, Ralf Butzow
• Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (Mod Pathol) Vol. 22 Issue 4 Pg. 570-8 (Apr 2009) ISSN: 1530-0285 [Electronic] United States
• PMID: 19329943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Protein Isoforms
• Tripartite Motif Proteins
• TRIM37 protein, human
• Ubiquitin-Protein Ligases

Topics

• CpG Islands (genetics)
• DNA Methylation
• DNA Mutational Analysis
• Female
• Humans
• Immunohistochemistry
• Loss of Heterozygosity
• Mulibrey Nanism (complications, genetics)
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Protein Isoforms (genetics, metabolism)
• Thecoma (genetics, metabolism, pathology)
• Tissue Array Analysis
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases