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.

TRIM37 promotes epithelial-mesenchymal transition in colorectal cancer

“…The TRIMs family has been identified to be involved in the progression, transformation, autophagy and metastasis of cancer (22–26). Previous studies have demonstrated altered expression levels of TRIM37 in breast and ovarian cancer, which confirmed its oncogenic function (8,9). The present study used RT-qPCR, immunostaining and western blotting to determine that the increased expression of TRIM37 occurred at the transcriptional and post-transcriptional levels in CRC, suggesting that it may contribute to the progression of malignancies.…”

“…TRIM37 was also revealed to be associated with polycomb repressive complex 2, and may lead to extensive changes in gene expression, including the silencing of some tumor suppressor genes (8). Previous studies revealed that TRIM37 may undergo amplification in ovarian cancer (9) and may promote transformation in breast cancer (8). Additionally, the upregulation of TRIM37 promoted the growth and migration of cancer cells of pancreatic cancer (10).…”

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

“…Mulibrey ( mu scle, li ver, br ain, and ey e) nanism is a rare, autosomal recessive growth disorder with prenatal onset that includes severe growth retardation, distinct dysmorphic features, constrictive pericarditis, hepatomegaly, male infertility, insulin resistance, and metabolic deficiencies (19,20). There are approximately 130 cases known worldwide with 89 originating from Finland (19).…”

“…There are approximately 130 cases known worldwide with 89 originating from Finland (19). Mulibrey nanism is caused by biallelic mutations in TRIM37 on chromosome 17q22.…”

“…A systematic review revealed a total of 210 tumors in 66 of the 89 (74%) reported Finnish patients (20). Benign tumors included cysts within various organs, peliosis of the liver, adrenal adenoma, parathyroid adenoma, thyroid nodules, pancreatic cystadenoma, renal angiomyolipoma, ovarian fibrothecoma, pheochromocytoma, and central nervous system Langerhans cell histiocytosis (19). Thirteen (15%) of these patients developed malignant tumors, including WT (n = 5; median age 2.5 years, range 2.2 – 3.7 years), renal papillary carcinoma (n = 3, median age 22.3 years, range 17 – 28 years), papillary thyroid carcinoma (n = 3; median age 32.1, range 28 – 40), and single cases of medullary thyroid carcinoma, ovarian carcinoma, endometrial carcinoma, and acute lymphoblastic leukemia (19).…”