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Gynecological Tumors in Mulibrey Nanism and Role for RING Finger Protein TRIM37 in the Pathogenesis of Ovarian Fibrothecomas

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Gynecological Tumors in Mulibrey Nanism and Role for RING Finger Protein TRIM37 in the Pathogenesis of Ovarian Fibrothecomas Modern Pathology (2009) 22, 570–578 & 2009 USCAP, Inc All rights reserved 0893-3952/09 $32.00 www.modernpathology.org Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas Susann Karlberg1,2, Marita Lipsanen-Nyman2, Heini Lassus1, Jukka Kallija¨rvi3,4,5, Anna-Elina Lehesjoki3,4,5 and Ralf Butzow1,6 1Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland; 2Children’s Hospital, University of Helsinki, Helsinki, Finland; 3Folkha¨lsan Institute of Genetics, Helsinki, Finland; 4Department of Medical Genetics, University of Helsinki, Helsinki, Finland; 5Neuroscience Center, University of Helsinki, Helsinki, Finland and 6Department of Pathology, University of Helsinki, Helsinki, Finland 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. Modern Pathology (2009) 22, 570–578; doi:10.1038/modpathol.2009.13; published online 27 February 2009 Keywords: ovarian tumor; fibrothecoma; hereditary predisposition; hereditary disorder; TRIM37; Mulibrey nanism Mulibrey nanism is an autosomal recessive inher- diagnosed. Mulibrey nanism is caused by mutations ited disorder characterized by prenatal-onset growth in the TRIM37 gene on chromosome 17q22–23.5–7 It failure, distinct craniofacial features, perimyocar- codes for a protein belonging to the TRIM (TRIpar- dial heart disease, insulin resistance and a mainly tite Motif; previously designated RBCC for RING-B- unaffected psychomotor development.1–4 This dis- box-Coiled-coil) protein family, members of which order is enriched in Finland where 88 of the are often involved in developmental regulation and approximately 130 known patients have been oncogenesis.6 The wild-type TRIM37 protein loca- lizes to peroxisomes in cultured human and rodent cells8 and possesses ubiquitin E3 ligase activity.9 Correspondence: Dr R Butzow, MD, PhD, Department of Pathol- Fifteen disease-associated mutations in the TRIM37 ogy, University of Helsinki, P.O. Box 21, FIN 00014, Helsinki, gene have been published.6,7,9–12 The recessive Finland. E-mail: [email protected] nature of the disorder and the fact that all but four Received 11 December 2008; revised 2 February 2009; accepted of the disease-associated mutations are truncating 3 February 2009; published online 27 February 2009 suggest a loss-of-function modality underlying the TRIM37 in ovarian fibrothecomas S Karlberg et al 571 pathogenesis of Mulibrey nanism. The physiological The study material was as follows: formalin-fixed function of TRIM37 and the exact molecular paraffin-embedded tumors from patients with Muli- mechanisms leading to Mulibrey nanism are brey nanism (n ¼ 12); freshly frozen samples (n ¼ 15) unknown. from sporadic fibrothecomas for mutation analysis; The development of reproductive organs seems to mainly formalin-fixed paraffin-embedded samples be unaffected in Mulibrey nanism. However, female with some freshly frozen samples for LOH analysis patients with Mulibrey nanism are infertile and they and methylation studies, 33 and 31 samples, all develop ovarian failure before the age of 30 respectively. Owing to limitations in the availability years.13 We have previously reported that female of tumor tissue, the study material used in different patients with Mulibrey nanism are at a very high analyses was only partly overlapping. risk of developing ovarian sex cord–stromal tu- Two tissue arrays were prepared and analyzed: (1) mors.13 However, these tumors have not been a macroarray consisting of core tissue biopsies previously characterized in detail. In this study, (4 mm diameter each) from Mulibrey fibrothecomas we describe the clinical and pathological character- (n ¼ 12) and (2) a microarray from sporadic fibrothe- istics of all ovarian tumors associated with Mulibrey comas (n ¼ 25), which was constructed as described nanism. There are many examples of genes respon- previously.15 Four core tissue biopsies were ob- sible for hereditary tumor syndromes being defec- tained from each specimen. tive also in respective sporadic tumors. Therefore, we analyzed the TRIM37 gene and protein expres- sion and looked for somatic mutations, loss of Immunohistochemistry heterozygosity (LOH) and promoter methylation of From the tumor tissue array blocks and normal the gene in sporadic fibrothecomas. ovary samples, 5-mm sections were cut with a microtome. The primary antibody used for the Materials and methods Mulibrey fibrothecomas was anti-inhibin-a (MCA951S; Serotec, Oxford, UK; 1:80). For TRIM37 Patients with Mulibrey Nanism staining of sporadic fibrothecomas and normal ovary samples, an antigen affinity-purified fraction of After characterization of Mulibrey nanism in the rabbit antiserum (60 mg/ml) raised against a synthetic mid-1970s, a nationwide register of patients was peptide (FPDGEQIGPEDLSFNTDENSGR) corre- established in Finland, and the follow-up of the sponding to the C terminus of the TRIM37 protein patients has been performed and organized at the was used.8 Normal rabbit IgG (Vector Laboratories, Children’s Hospital, Helsinki University Central Burlingame, CA, USA) was used as a negative Hospital, mainly by one of the authors (ML-N). control. TRIM37 staining was carried out as pre- The complete records of 22 female patients 420 viously described,8 using Vectastain Elite kit (Vector years of age were reviewed for ovarian and other Laboratories) according to the manufacturer’s proto- gynecological tumors. Age at primary diagnosis or col. Immunostaining of inhibin-a was performed in recurrences was recorded. The surgical reports were a Dako TechMate 500 automated staining machine. reviewed for tumor size, multifocality and bilater- ality. The study was approved by the institutional ethical review board at the University of Helsinki, Mutation Analysis of TRIM37 cDNA in Sporadic and all subjects gave informed consent. Fibrothecomas From freshly frozen samples of sporadic fibrotheco- Tissue Samples mas (n ¼ 15), messenger RNA was extracted using the Oligotex mRNA midi kit (Qiagen, Hilden, All tissue samples were reviewed by a gynecological Germany). cDNA was synthesized using M-MLV pathologist (RB) and the observed tumors were reverse transcriptase (Promega, Madison, WI, USA) classified according to the criteria of WHO.14 The and random hexamers (Promega) according to the formalin-fixed and paraffin-embedded samples were manufacturer’s protocols. Seven overlapping frag- obtained from the archives of the Department of ments covering the whole open-reading frame of Obstetrics and Gynecology, Helsinki University TRIM37 were amplified by polymerase chain reac- Central Hospital. The freshly frozen tumor speci- tion (PCR) using primers and conditions as before.6 mens were collected at the time of surgery, snap The resulting PCR products were evaluated on 1% frozen in liquid nitrogen and stored at À801C. ethidium bromide-stained agarose gels, purified Normal ovary samples (n ¼ 3) came from women (PCR purification kit; Qiagen) and sequenced using (o35 years) for whom oophorectomy was performed the ABI PRISM Dye Terminator, the ABI PRISM because of cervical carcinoma without neoadjuvant dRhodamine cycle sequencing Kit (PerkinElmer, treatment. Normal tissue complementary DNAs Foster City, CA, USA) or Big Dye Terminator (cDNAs) came from human multiple tissue cDNA (Applied Biosystems, Foster City, CA, USA) and panels (Human MTC panel I and Human MTC panel run on an ABI Prism 310 Genetic Analyzer (Perkin II; Clontech, Mountain View, CA, USA). Elmer). Both strands were sequenced and the Modern Pathology (2009) 22, 570–578 TRIM37 in ovarian fibrothecomas S Karlberg et al 572 obtained sequence information
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