Profiling of differential gene expression in leomyoma and myometrium in primary and recurrent uterine fibroids

   Background. The lack of clarity regarding the mechanisms underlying the pathogenesis of leiomyomas and their recurrence presents a significant challenge in developing a personalized approach to effective treatment, particularly for women in their reproductive years.

   Aim: to investigate the differential gene expression patterns in leiomyomas and unaltered myometrium, with the goal of developing a personalized strategy for predicting the progression and treatment of leiomyomas.

   Methods. The research material comprised samples of leiomyomas, myometrial tissue, and peripheral blood obtained from 32 patients diagnosed with primary or recurrent uterine fibroids, with 22 and 10 cases, respectively. Blood and leiomyomas samples were subjected to analysis for mutations in the MED12 gene employing the Sanger sequencing technique. Expression profiles of 18 potential genes were evaluated through reverse transcription and polymerase chain reaction on tissue samples obtained from leiomyomas and unaltered myometria.

   Results. The findings suggest that in both primary and recurrent leiomyoma nodules with somatic MED12 mutations, there is an upregulation of the expression of GRPR, TYMS, RANKL and MMP11 genes compared to their counterparts in morphologically normal myometrium. Conversely, in recurrent leiomyomas without MED12 somatic mutations, there is an increase in the expression of the GRPR and RANKL genes. Meanwhile, in primary leiomyomas, there is a decrease in the expression of these same genes when compared to the corresponding myometrial tissue.

   Conclusion. The genes GRPR, TUMS, RANKL and WMP11 represent promising targets for the development of a personalised approach to the prediction of the course and management of uterine fibroids.

1. Klinicheskiye rekomendatsii. Mioma matki [Clinical guidelines. Uterine myoma]. Moscow, 2024. https://cr.minzdrav.gov.ru/preview-cr/257_2 (In Russ.)

2. Ginekologiâ : nacionalʹnoe rukovodstvo. Pod red. G. M. Savelʹevoj, G. T. Suhih, V. N. Serova, V. E. Radzinskogo, I. B. Manuhina [Gynecology : national guidelines. Ed. G. M. Savelyeva, G. T. Sukhikh, V. N. Serov, V. E. Radzinsky, I. B. Manukhin]. – 2^nd ed. reworked and additional – Moscow: GEOTAR-Media, 2022. – 1008 p. (In Russ.)

3. Stewart E. A., Cookson C. L., Gandolfo R. A., Schulze-Rath R. Epidemiology of uterine fibroids : a systematic review. BJOG. 2017; 124(10):1501–1512. doi: 10.1111/1471-0528.14640.

4. Narayanan D. L., Phadke S. R. A novel variant in MED12 gene: Further delineation of phenotype». Am. J. Med. Genet. Part A. 2017;173(8): 2257–2260. doi: 10.1002/ajmg.a.38295.

5. Mittal P., Shin Y., Yatsenko S. A., et al. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J. Clin. Invest. 2015;125(8): 3280–3284. doi: 10.1172/JCI81534.

6. Burmenskaya O.V., Trofimov D.Yu., Kometova V.V., et al. Razrabotka i opyt ispol’zovaniya transkriptsionnoy signatury genov v diagnostike molekulyarnykh podtipov raka molochnoy zhelezy [Development and experience of using the transcriptional gene signature in the diagnosis of molecular breast cancer subtypes]. Akusherstvo i Ginekologiya [Obstetrics and gynecology]. 2020;2: 132-40. (In Russ.). doi: 10.18565/aig.2020.2.132-140

7. Schmittgen T.D., Zakrajsek B.A., Mills A.G., et al. Quantitative Reverse Transcription – Polymerase Chain Reaction to Study mRNA Decay: Comparison of Endpoint and Real-Time Methods. Anal Biochem. 2000; 285: 194-204.