Abstract 1998: Exome sequencing and SNP array analysis of HLRCC syndromic uterine leiomyomas.
Authors: Kämpjärvi Kati , Mehine Miika , Vahteristo Pia , Aaltonen Lauri A. 
Published: August 2014

Abstract
Uterine leiomyomas (fibroids) affect approximately 70% of women by the age of 50 years and thus are the most frequent tumors of the female reproductive tract. Fibroids are benign tumors originating from the smooth muscle cells of the uterus. They may cause various symptoms including abdominal pain, abnormal bleeding, and pregnancy complication, and they are the most common cause for hysterectomy. Our recent study identified somatic mutations in mediator complex subunit 12 (MED12) in as many as 70% of sporadic fibroids. Traditionally, fibroids have been considered rather stable, although some recurrent cytogenetic rearrangements affecting mainly chromosomes 7q, 12q15, and 6p21 have been reported. Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC, OMIM 150800) is an autosomal dominant cancer syndrome which predisposes to cutaneous and uterine leiomyomas, and renal cell cancer. Syndrome is caused by heterozygous germline mutations in the tumor suppressor gene fumarate hydratase (FH) at 1q42.1. The gene encodes fumarase, which catalyzes the hydratation of fumarate to L-malate in mitochondrial tricarboxylic acid cycle. Cutaneous and uterine leiomyomas are the most prevalent lesions with the syndrome and present typically at the age of 25 to 30 years. The aim of this study was to systematically characterize the genomic profile of FH deficient fibroids. For this, we analyzed altogether 10 fibroids and their corresponding myometrial samples from two Finnish HLRCC-family members and one sporadic leiomyoma sample with two somatic changes in FH by exome sequencing and SNP array analyses. To identify somatic variants, exome data from the tumors was filtered against the data from the respective myometrial samples as well as 93 Finnish individuals from the 1000 Genomes Project, 62 in-house controls, and all known variants in the dbSNP database. Altogether only 18 validated somatic mutations were observed in the exome data. All the variants were unique; they were observed only in one sample and the respective genes did not harbor additional changes in other tumors. No variations in genes commonly mutated in malignant tumors e.g. TP53, Rb or PTEN were observed. Neither were MED12 mutations, suggesting that mutations in MED12 and biallelic FH inactivation are mutually exclusive. In the SNP array analysis most of the tumors were found to carry large (&gt;5 Mb) aberrations. The only recurrent change was the deletions at the FH locus. Deletions at 7q, which are frequently observed in sporadic uterine leiomyomas, were not present in these FH deficient tumors. To summarize, exome sequencing and SNP array analyses of 11 FH deficient tumors did not reveal any recurrent somatic variations in addition to the changes at the site of FH at 1q42. Loss of FH function damages the tricarboxylic acid cycle and causes a severe metabolic stress for the cells. This may be sufficient to induce formation of these benign lesions of the uterus.
Citation Format: Kati Kämpjärvi, Miika Mehine, Pia Vahteristo, Lauri A. Aaltonen. Exome sequencing and SNP array analysis of HLRCC syndromic uterine leiomyomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1998. doi:10.1158/1538-7445.AM2013-1998