Abstract 2461: Molecular classification and clinical characterization of a large uterine leiomyoma patient cohort
Authors: Mäkinen Netta , Heinonen Hanna-Riikka , Pasanen Annukka , Tolvanen Jaana , Bramante Simona , Mehine Miika , Sjöberg Jari , Heikinheimo Oskari , Bützow Ralf , Aaltonen Lauri A. 
Published: July 2017

Abstract
Uterine leiomyomas (ULs), benign smooth muscle tumors, represent one of the most common neoplasms in women with an estimated prevalence varying from 20% to over 70% during the reproductive years. Approximately every fourth woman with ULs has clinically relevant lesions, which cause morbidity and thus require treatment. Still today, hysterectomy is the primary treatment option for ULs worldwide, and remarkably, their annual societal costs exceed those of colon and breast cancer combined. Our previous findings, derived from the use of high-throughput technologies, suggest that there are at least three distinct molecular UL subclasses, each displaying a characteristic genetic driver aberration and unique global gene expression profile: MED12 (mediator complex subunit 12) mutation-positive, HMGA2 (high mobility group AT-hook 2)-overexpressing, and FH (fumarate hydratase)-deficient ULs. The aim of this study is to examine the molecular subclasses, their respective proportions, and clinical characteristics in a large UL patient cohort. The study material consists of 1026 ULs and corresponding normal myometrium tissue from 322 patients, who had ultrasound-diagnosed ULs and underwent hysterectomy in Helsinki University Hospital, Finland between October 2013 and June 2016. From each uterus, we harvested all feasible ULs ≥1 cm in diameter and a piece of the corresponding normal myometrium tissue. The location of the collected samples in the uterus, their size, and any observed special characteristics were carefully documented at the time of sample removal. In addition, comprehensive clinical information of the patients was obtained from medical and pathology reports, as well as from a questionnaire, and the histopathology of all lesions were characterized according to the WHO 2014 criteria. All collected ULs have been systematically screened for MED12 mutations by Sanger sequencing. Overexpression of HMGA2 typically arises from a chromosomal translocation, and deletions at FH locus suggest the presence of potential biallelic FH inactivation. Therefore, HMGA2-overexpressing and FH-deficient ULs have tentatively been identified using a high-density customizable Infinium® HumanCore-24+ BeadChip with over 305,000 markers. Currently, the data analyses are ongoing. Sufficient numbers of well-documented high-quality samples are a prerequisite for successful research. We hypothesize that ULs can emerge through several distinct molecular mechanisms that contribute to different biological and clinicopathological features and response to treatment. Their molecular classification and further characterization will lead to increased knowledge on UL genesis as well as improved management of the disease.
Citation Format: Netta Mäkinen, Hanna-Riikka Heinonen, Annukka Pasanen, Jaana Tolvanen, Simona Bramante, Miika Mehine, Jari Sjöberg, Oskari Heikinheimo, Ralf Bützow, Lauri A. Aaltonen. Molecular classification and clinical characterization of a large uterine leiomyoma patient cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2461. doi:10.1158/1538-7445.AM2017-2461