Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy

Abstract

STUDY QUESTION What are the distributions and associated clinical characteristics of mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2) and fumarate hydratase (FH) aberrations in uterine leiomyomas from fertile-aged myomectomy patients? SUMMARY ANSWER These driver mutations account for the majority (83%) of tumours in fertile-aged patients. WHAT IS KNOWN ALREADY Alterations affecting MED12, HMGA2 and FH account for 80–90% of uterine leiomyomas from middle-aged hysterectomy patients, while the molecular background of tumours from young myomectomy patients has not been systematically studied. STUDY DESIGN, SIZE, DURATION A retrospective series of 361 archival uterine leiomyoma samples from 234 women aged ≤45 years undergoing myomectomy in 2009–2014 was examined. Associations between the molecular data and detailed clinical information of the patients and tumours were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS DNA was extracted from formalin-fixed paraffin-embedded samples and MED12 exons 1 and 2 were sequenced to identify mutations. Level of HMGA2 expression was evaluated by immunohistochemistry. Biallelic FH inactivation was analysed with 2-succinylcysteine staining, which is an indirect method of assessing FH deficiency. All patients’ medical histories were reviewed, and clinical information of patients and tumours was combined with molecular data. MAIN RESULTS AND THE ROLE OF CHANCE The median age at operation was 34 years. The majority (58%) of patients were operated on for a single leiomyoma. Known driver mutations were identified in 83% of tumours (71% MED12; 9% HMGA2; 3% FH). In solitary leiomyomas, the MED12 mutation frequency was only 43%, and 29% were wild-type for all driver alterations. MED12 mutations were associated with multiple tumours, smaller tumour size and subserosal location. LIMITATIONS, REASONS FOR CAUTION Although comprehensive, the study is retrospective in nature and all samples have been collected for routine diagnostic purposes. The use of paraffin-embedded samples and immunohistochemistry may have led to an underestimation of mutations. Due to the limited sample size and rarity of especially FH-deficient leiomyomas, the data are partly descriptive. WIDER IMPLICATIONS OF THE FINDINGS The contribution of driver mutations in leiomyomas from young myomectomy patients is comparable to tumours obtained from hysterectomies of mostly middle-aged women. Our results support the earlier findings that MED12 mutations are associated with multiple tumours, smaller tumour size and subserosal location. The study emphasizes the distinct molecular background of solitary leiomyomas, and more research is needed to clarify the underlying causes of the notable proportion of wild-type leiomyomas. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Academy of Finland (307773), the Sigrid Jusélius Foundation, the Cancer Foundation Finland and the iCAN Digital Precision Cancer Medicine Flagship. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A

Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment

“…No associations were observed between MED12 mutations and patient infertility, smoke consumption, BMI, history of pelvic inflammatory disease and chlamydia, hypertension, thyroid disorder, diabetes, oral contraceptive use, or family history of uterine fibroids ( 10 ). The observation that MED12 mutation–positive uterine fibroids are associated with a subserous location was subsequently confirmed in another large retrospective study that included 361 tumors from 234 myomectomy patients whose median age of 34 years also revealed that the MED12 mutation frequency in uterine fibroids from fertile-age women is comparable to that found in perimenopausal women ( 153 ). Altogether, these analyses support the relevance of MED12 driver mutations in the pathogenesis and clinical presentation of uterine fibroids.…”

3′RNA and whole‐genome sequencing of archival uterine leiomyomas reveal a tumor subtype with chromosomal rearrangements affecting either HMGA2, HMGA1, or PLAG1

“…15 Here, we performed 3 0 RNA-sequencing with 111 leiomyomas that had been previously classified as negative for a MED12 mutation, HMGA2 overexpression, and FH-deficiency by Sanger sequencing or immunohistochemistry. [16][17][18][19][20] Interestingly, we identified a subset of tumors to display expression features typically seen in leiomyomas with an HMGA2 rearrangement, including PLAG1 overexpression. Gene expression profiling divided the samples further into three separate clusters, one characterized by high expression of HMGA2, one by upregulation of HMGA1, and one by exceptionally high expression of PLAG1 but low expression of both HMGA2 and HMGA1.…”

A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase

“…1a ). To study this further, we analyzed another previously examined dataset of 360 unselected leiomyomas [ 20 ] and discovered three additional tumors with AKR1B10 expression and no known driver defects. These twelve tumors are hereafter referred to as AKR1B10hi leiomyomas.…”

“…The initial discovery set consisted of 141 leiomyomas with variant histopathology [ 18 ]. The validation set included 360 unselected leiomyomas, of which 12 displayed variant histopathology [ 20 ]. Three samples in the validation set were also included in the discovery set and therefore omitted from the latter cohort.…”

“…The total sample series thus included 498 tumor samples, of which 348 displayed conventional and 150 variant histopathology. The status of MED12 , HMGA2, and FH has been determined in previous studies [ 7 , 18 – 20 ]. See Supplementary Table 1 for an overview of the samples.…”