Abstract 3514: MED12 and FH mutations in HLRCC associated uterine leiomyomas
Authors: Kämpjärvi Kati , Mäkinen Netta , Mehine Miika , Tolvanen Jaana , Heikkinen Tuomas , Bützow Ralf , Aaltonen Lauri A. , Vahteristo Pia 
Published: May 2015

Abstract
Uterine leiomyomas (fibroids) are benign tumors which originate from the smooth muscle cells of the myometrium. Almost 70% of women are affected by these tumors by the age of 50. Even though uterine leiomyomas are benign, they can cause difficult symptoms and are the most common indication for hysterectomy. Most uterine leiomyomas are sporadic and up to 70% of these lesions harbor very specific mutations in MED12 (mediator complex subunit 12). All MED12 mutations observed in uterine leiomyomas have been missense or insertion deletion mutations retaining the open reading frame. Uterine leiomyomas occur also in the context of Hereditary Leiomyomatosis and Renal Cell Cancer syndrome (HLRCC, OMIM # 150800). In addition to uterine leiomyomas, the syndrome predisposes individuals to cutaneous leiomyomas and renal cell cancer. HLRCC is an autosomal dominant syndrome caused by heterozygous germline mutations in FH (fumarate hydratase). The gene is classified as a tumor suppressor and according to Knudson's two-hit hypothesis, syndrome related tumors display biallelic inactivation of FH. Recently, we reported 3/34 uterine leiomyomas from HLRCC patients to harbor somatic mutations in MED12. Loss of heterozygosity (LOH) at the FH locus was assessed from the tumors, and interestingly none of the MED12 mutation positive tumors showed biallelic inactivation of FH through LOH. Exome sequencing of seemingly sporadic uterine leiomyomas revealed also one patient to carry a truncating germline mutation in FH. The FH and MED12 loci from the uterine leiomyomas of this patient were further studied with direct sequencing and LOH assessment. Tumors had different MED12 mutations and none of them harbored a somatic mutation or displayed LOH as a second hit at FH locus. The aim of this study is to clarify the role of MED12 in HLRCC syndrome associated uterine leiomyomas and to analyze whether MED12 mutations and biallelic inactivation of FH are truly mutually exclusive. A tissue microarray including uterine leiomyomas from HLRCC patients will be constructed and FH inactivation will be analyzed with immunohistochemical stainings. Expression analyses of the tumors harboring somatic MED12 mutation and FH mutation in germline will show whether these tumors cluster together with MED12 mutation positive tumors, tumors with biallelic FH inactivation, or if they form a separate cluster. Results of these analyses will reveal if there are two distinct molecular mechanisms behind the development of uterine leiomyomas in HLRCC patients; one dependent on the biallelic inactivation of FH and the other on the altered function of MED12.
Citation Format: Kati Kämpjärvi, Netta Mäkinen, Miika Mehine, Jaana Tolvanen, Tuomas Heikkinen, Ralf Bützow, Lauri A. Aaltonen, Pia Vahteristo. MED12 and FH mutations in HLRCC associated uterine leiomyomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3514. doi:10.1158/1538-7445.AM2014-3514