MED12 Mutations in Uterine and Extrauterine Smooth Muscle Tumors
Katherine Schwetye, John Pfeifer, Eric Duncavage. Washington University in St Louis, St Louis, MO
Background: A recent report of exome sequencing in uterine leiomyomas showed that a majority (70%) harbor mutations in the mediator complex subunit 12 gene (MED12). These mutations occur almost exclusively in exon 2, and have been substantiated by several subsequent studies. While other, recurrent genetic abnormalities have previously been identified in leiomyomas (del 7q, trisomy 12, rearrangements of 12q14), these occur with a lower frequency. MED12 exon 2 mutations represent the most common genetic abnormalities of uterine leiomyoma to date. We sought to determine the incidence of MED12 exon 2 mutations in intra-and extrauterine smooth muscle tumors.
Design: We identified cases of leiomyomas, leiomyosarcomas, and smooth muscle tumors of uncertain malignant potential (STUMPs) in intra- and extrauterine sites resected from 1994-2012. Cellular areas of tumor were identified by histological examination, and formalin-fixed tissue was micro-punched from corresponding paraffin-embedded blocks. DNA was extracted and PCR amplified using primers specific for MED12 exon 2. Amplified DNA was then bi-directionally Sanger sequenced and the resulting traces analyzed for sequence variation.
Results: We identified MED12 exon 2 mutations in 9/18 (50%) classical uterine leiomyomas and 0/5 cellular, atypical or symplastic subtypes. MED12 exon 2 mutations were identified in 2/20 (10%) extra-uterine leiomyoma/leiomyomatosis, 5/20 uterine leiomyosarcomas (25%), 2/24 (8%) extra-uterine leiomyosarcomas and 1/8 (12%) intra-and extrauterine STUMPS. Mutations were predominantly single-base pair substitutions, most often affecting codon 44, and rare deletions.
Conclusions: Our results show that exon 2 MED12 mutations are common in classical uterine leiomyomas, but are uncommon in subtypes of leiomyomas (0%). Similarly, MED12 mutations are less common in extrauterine leiomyomata (10%); intra- and extrauterine STUMPS (12.5%); uterine leiomyosarcoma (25%); and extrauterine leiomyosarcoma (8%). These findings demonstrate that MED12 exon 2 mutations are present in various tumors of smooth muscle derivation, albeit at a lower frequency than classical leiomyomas. Further, molecular testing for MED12 mutations may be a useful adjunct to confirm the diagnosis of uterine and extra uterine smooth muscle tumors.
Category: Gynecologic & Obstetrics
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 184, Monday Morning