MED12 mutation frequency in unselected sporadic uterine leiomyomas

Capsule:
MED12 mutations inversely correlate with leiomyoma size; in this study where size bias is carefully controlled, over 80% of uterine leiomyomas display a MED12 mutation.

Authors:
Hanna-Riikka Heinonen, M.B., Nanna S. Sarvilinna, M.D., Ph.D., Jari Sjöberg, M.D., Ph.D., Kati Kämpjärvi, M.Sc., Esa Pitkänen, Ph.D., Pia Vahteristo, Ph.D., Netta Mäkinen, M.Sc., Lauri A. Aaltonen, M.D., Ph.D.

Volume 102, Issue 4, Pages 1137-1142

Abstract:

Objective:
To determine the frequency of mediator complex subunit 12 (MED12) mutations in well-documented, prospectively collected, unselected series of sporadic uterine leiomyomas to better understand the contribution of MED12 mutations in leiomyoma genesis.

Design:
Mutation analysis of two prospectively collected sample series.

Setting:
Department of gynecology in university hospital and medical genetics research laboratory.

Patient(s):
164 uterine leiomyomas from 28 patients (13 consecutive and 15 unselected patients) undergoing hysterectomy.

Intervention(s):
MED12 mutation screening by direct sequencing, and clinical data collection.

Main Outcome Measure(s):
MED12 mutation status and various clinical variables.

Result(s):
MED12 mutations were found in 73 (83.0%) of 88 and 65 (85.5%) of 76 of uterine leiomyomas from the consecutive and unselected patient series, respectively. Smaller tumor size and a larger number of tumors correlated with positive MED12 mutation status.

Conclusion(s):
The frequency of MED12 mutations in our prospectively collected uterine leiomyoma sets was higher than in previous works. This is in keeping with the concept that MED12 mutation-positive tumors tend to be smaller in size than MED12 mutation-negative tumors. The results highlight the central role of MED12 mutations in uterine leiomyoma genesis.

  • Lauri Aaltonen

    Thank you for your kind comment. You are
    absolutely right that the different molecular mechanisms lead to fibroids with
    somewhat different biological and clinical features, and it would indeed be surprising
    if these differences didn´t matter in view of drug response. One obvious
    challenge in this context is that one uterus may harbour lesions that have
    arisen through different mechanisms.

  • Shvetha Zarek

    Thank you to this esteemed group for an excellent study on the frequency of MED12 mutations in sporadic uterine leiomyoma. At NIH we treat a number of HLRCC kindreds and it is interesing to confirm that concomitant germline FH mutation and MED12 mutations are rare. Also of note was that MED 12 positive tumours are generally smaller than MED 12 negative tumors. This highlights a number of questions about the pathophysiology of the different mutations (differences in ECM proliferation?) and how medical treatments like ulipristal acetate could be more efficacious for certain mutation types. Thank you for a thought provoking study.

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