[35] MED12 Exon 2 Mutation Analysis in Different Subtypes of Smooth Muscle Tumors Confirms Genetic Heterogeneity

Marieke A de Graaff, Karoly Szuhai, Anne-Marie Cleton-Jansen, Judith VMG Bovee. Leiden University Medical Center, Leiden, Netherlands

Background: Recently mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been described in 50-70% of uterine leiomyomas (fibroids); the recurrent nature of these mutations suggests an important role in their pathogenesis. MED12 is involved in regulation of transcription and Wnt-signaling. So far, little is known about the pathogenesis of the different subtypes of extra-uterine leiomyomas and of the malignant counterpart leiomyosarcoma.
Design: We therefore performed mutation analysis using PCR and direct sequencing of exon 2 of MED12 and immunohistochemistry for β-catenin, using 70 tumors of 65 different patients; 19 uterine leiomyomas, 6 abdominal leiomyomas, 5 angioleiomyomas, 5 leiomyomas of soft tissue, 5 piloleiomyomas, 7 uterine leiomyosarcomas and 23 leiomyosarcomas of soft tissue.
Results: In 11 of 19 uterine leiomyomas (56%) a mutation in MED12 was identified, which is consistent with the literature. One of 6 abdominal leiomyomas, of which a primary uterine origin cannot be excluded, displayed a homozygous mutation. Mutations were absent in all other extra-uterine leiomyomas. Of the 30 leiomyosarcomas, only one uterine leiomyosarcoma harbored a mutation. Beta-catenin immunohistochemistry revealed nuclear staining in 10 of 40 leiomyomas and 3 of 30 leiomyosarcomas. Among the mutated uterine leiomyomas, 54% displayed nuclear positivity compared to none of the non-mutated uterine fibroids; and 80% of the piloleiomyomas were positive.
Conclusions: As no MED12 alterations are found in convincing extra-uterine leiomyomas and leiomyosarcomas of soft tissue these tumors probably arise through different pathogenetic mechanisms emphasizing the genetic heterogeneity of smooth muscle tumors. Since only 54% of the MED12 mutated uterine leiomyomas displayed nuclear β-catenin, this suggests that in addition to canonical Wnt-signaling other pathways are responsible for tumorigenesis in MED12 mutated tumors. The β-catenin pathway might be involved in the development of sporadic piloleiomyomas as 80% showed nuclear β-catenin immunopositivity. Thus, our results confirm genetic heterogeneity and exclude a role for MED12 in soft tissue smooth muscle tumors.
Category: Bone & Soft Tissue

Monday, March 4, 2013 1:00 PM

Poster Session II # 4, Monday Afternoon


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