Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 17 | Issue 4 | Year 2023

The Genetic Correlation of Ultrasonic Uterine Fibroid Mapping

Hisham Arab1

Director of Women’s Health Department, Dr Arab Medical Center, Jeddah, Makkah, Saudi Arabia

Corresponding Author: Hisham Arab, Director of Women’s Health Department, Dr Arab Medical Center, Jeddah, Makkah, Saudi Arabia, Phone: +966505642712, e-mail:


Uterine fibroids (UFs) or leiomyomas (LM) are common benign neoplasms of the uterus. UFs have many complications and can negatively affect the women’s quality of life, and their management can get interventional. This review discusses the epidemiology, etiology, pathogenesis, and genetic origin of UFs as well as the contributing epigenetic factors to their development. We correlated some of the driving genetic factors of fibroids with their presentation or location on ultrasound clinically.

How to cite this article: Arab H. The Genetic Correlation of Ultrasonic Uterine Fibroid Mapping. Donald School J Ultrasound Obstet Gynecol 2023;17(4):290–294.

Source of support: Nil

Conflict of interest: None

Keywords: Epigenetic, Genetic, Mapping, Ultrasound, Uterine fibroids


Uterine fibroids (UF), also known as leiomyomas (LM), are benign uterine smooth muscle tumors, which are the most frequent tumors of the female genital tract.1 UFs originate from the myometrium and are usually the result of clonal growth of a single cell. The growth of UFs depends on the levels of progesterone and estrogen; thus, they are affected by the woman’s life course, menstrual cycle phases, and the use of hormone-altering drugs as contraceptives.2,3

Despite benign tumors, UFs can negatively affect women’s health and cause many complications such as infertility, abdominal distension, pelvic pressure and pain, urinary incontinence, severe anemia, dysmenorrhea, irregular and heavy periods, and early and recurrent miscarriages. However, symptoms are usually unclear on presentation.4,5 Sometimes, fibroids are found accidentally during imaging or routine pelvic examination. The most common symptoms of UFs include low back pain, bowel dysfunction, constipation, pelvic pressure, dyspareunia, urinary retention, urinary frequency, urgency, and abnormal uterine bleeding.6

The incidence and prevalence rates of UF vary among reports. In 2019, UFs incidence was reported to have increased by 6.87% since 1990 to 241.18 per 100,000 women. The majority of the surveyed 204 countries had an increase in prevalence, incidence, and years lived with disability (YLDs) rate of UFs. The highest incidence was reported in women aged 35–39, and the highest prevalence was among women of 40–44 years of age.7 Similarly, it was reported that UFs are prevalent among around 40–60% of women under 35 and 70–80% of 50-year-old women and older.8 It is estimated that one in four women within the reproductive age have UFs.9

The causative factors and the mechanisms underlying the transformation of smooth muscle cells into UF are still under investigation. However, it is known that UF results from a complex myriad of factors, including genetic abnormalities, hormonal imbalance, epigenetics, muscle contractions, and lower levels of oxygen associated with menstruation, as well as childbirth.10,12 According to the American Academy of Family Physicians (AAFP), obesity, African descent, nulliparity, earlier onset of menarche, and a family history of UFs are high-risk factors for developing UFs. Factors including smoking, late menarche, increased parity, and use of oral contraceptives are considered low-risk factors for UFs development.6 The association between vitamin D deficiency and developing UFs is also under study.13 In three clinical studies, vitamin D levels were lower in patients with UFs compared to healthy patients. Decreased vitamin D levels may increase the expression of genes linked to UF pathogenesis.14


Uterine fibroids (UFs) are classified into intramural, subserosal, submucosal, and pedunculated UFs.15 The International Federation of Gynecology and Obstetrics (FIGO) classified UFs based on their location into eight types as demonstrated in Figure 1. In short, type 0 refers to intracavity lesions attached to the endometrium by a narrow stalk. If type 0 lesions had an intramural portion, they would be classified as type 1 or 2, whereas type 3 lesions border the endometrium while being completely extracavitary. Type 4, however, is located entirely in the myometrium, with no extension to the endometrial surface or the serosa. Lesion types 5, 6, and 7 are mirror images of submucosal UFs. UFs, including cervical lesions unrelated to the myometrium and lesions in the form of round or broad ligaments (without direct attachment to the uterus), are classified as type 8 lesions.16

Fig. 1: The International Federation of Gynecology and Obstetrics (FIGO) classification of UFs


Fibroids are primarily characterized by abnormal cell proliferation, suppressed apoptosis, deoxyribonucleic acid (DNA) instability, and excessive accumulation of extracellular matrix (ECM), among other biological pathways. The growth and development of UFs are partially influenced by a delicate balance between genes that control cell proliferation and those that regulate apoptosis.10

The underlying molecular mechanisms responsible for the tumorigenicity of smooth muscle cells remain elusive. Normal myometrium and fibroid tissue contain cells with self-renewal capacity, known as stem cells (SCs), that drive the physiological enlargement of the uterus during pregnancy. Genetic anomalies in SCs are thought to play a significant role in UF pathogenesis.17

Mediator complex subunit 12 (MED12) gene, the high mobility group A2 gene (HMGA2), fumarate hydratase (FH) gene, and COL4A5-COL4A6 genes were identified as the leading players responsible for UF development. In around 70–75% of UF patients, somatic mutations of the MED12 gene were detected. An increased expression of the HMGA2 gene was noticed in samples from UF patients.17 HMGA2 aberrations trigger the pathogenesis of UFs by activating the pleomorphic adenoma gene 1 (PLAG1).18 It is believed that MED12 and HMGA2 genes interact together and result in the pathogenesis of UFs. Figure 2 illustrates the hypothesized genetic origin of UFs.

Fig. 2: The correlation between UF features and underlying genes

Fumarate hydratase (FH) gene mutations were proven to be associated with hereditary UFs. Somatic mutations of the FH gene result in the progression of UFs, and biallelic inactivation of the gene was found in UF patients.17 Diffuse UFs are attributed to specific deletions of the COL4A5-COL4A6 genes.19

Analysis of the genomic profile expression of UF cells revealed an abnormality in the Wnt/β-catenin, prolactin, and insulin-like growth factor (IGF) metabolic pathways. HMGA2 gene mutations result in the inhibition of the Wnt/β-catenin metabolic pathway. Additionally, mutations in the RAD51B gene, along with HMGA2 mutations, induce the inhibition of the Wnt metabolic pathway. Inactivation of the FH gene triggers the activation of the oncogenic transcription factor NRF2 (NFE2L2 gene). Another UF driver is the insulin receptor substrate 4 (IRS4) gene that induces deletions in the COL4A5 and COL4A6 genes.20,21

Omar et al. examined 15 progesterone target genes related to UF and determined their differential expression. They found that seven genes, namely CANP6, MT1E, ADHL5, ALDH1a1, KIK6, HHI, and CIDEc, exhibited a significant downregulation in UF cells. Whereas five genes (Bcl2, FOXO1A, SCGB2A2, CYP26a1, and MMP11) were upregulated in UF cells when treated with progesterone.22

In most UF patients, progesterone receptor (PR) changes have been shown to significantly impact DNA repair genes, such as EXO1 genes, p53, FH, RAD51L1, XRCC1, and XRCC4. Moreover, PRs can affect the function of downstream genes involved in cellular proliferation, apoptosis, cell cycle progression, tissue remodeling, and tumorigenesis. Estrogen receptors (ER), however, have been found with multiple aberrations that impact the DNA repair functions in UF cases.23 COMT gene has a role in the development of UFs.24 Regarding UFs proliferation, the PCNA gene contributes to the proliferation activity drive triggered by cyclin D–CDK4/6 activation.25 Likewise, the increased number of cell divisions and ECM production is responsible for UF tumor progression.26 The expression and growth of uterine smooth muscles is regulated by transforming growth factor-β (TGF-β). When comparing normal to UF tissue, it was found that the expression of TGF-β becomes almost twice as high in UF tissues.26Figure 2 demonstrates the correlation between genes and the main properties of UFs.


In addition to genetic factors, epigenetic changes and miRNAs might be involved in the pathophysiology of UFs. There is substantial evidence that miRNAs have a crucial role in cancer development and a variation between the expression profiles of miRNAs among healthy and UF tissues were noted.27 Moreover, miRNA–messenger ribonucleic acid (mRNA) regulatory networks are correlated to the tumorigenesis and progression of UFs.28 The role of seven miRNAs and their correlation with UF was determined as represented in Table 1.29

Table 1: The role of miRNAs in UF tumorigenesis and progression
miRNA Role and correlation with UFs
let-7 let-7 expression is higher in small UFs ≤3 cm
miR-15b Increased miR-15b and decreased reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression can help in the progression of UFs. miR-15b is upregulated in UF tissue
miR-29a The overexpression of miRNA-29a decreased the production of the ECM compound, and its levels were lower in UFs
miR-29b miR-29b can limit UF progression and excessive ECM accumulation. It is under-expressed in UFs
miR-29c miR-29c expression was suppressed in UFs, increasing the expression of genes responsible for collagen formation and UF progression
miR-197 miR-197 induces apoptosis, blocks cell migration, and inhibits cell proliferation. Its expression is lower in UFs
miRNA-200c miRNA-200C mediates the transcriptional regulation of genes controlling inflammation, the cell cycle, and nuclear factor kappa B (NF-κB) pathway. It is downregulated in UF tissue

Overall, studies highlight the significance of epigenetic changes, such as DNA methylation and histone modifications, in the development and growth of UFs. Although methylation and deregulated gene patterns vary in different reports, DNA hypermethylation was proven to have a vital role in the pathogenesis of UFs. Furthermore, there is evidence suggesting that the alteration of the epigenome and phenotype in UFs is a result of an abnormal DNA methylation/demethylation dynamic. A study examining the deregulation of ER response genes in LM using genome-wide DNA methylation and mRNA profiling revealed that UFs exhibited a distinct DNA methylation pattern compared to adjacent myometrium in 22 genes. For example, death-associated protein kinase 1 (DAPK1) was determined as a target gene for DNA hypermethylation in UFs. There is evidence supporting the involvement of 5-Hydroxymethylcytosine (5hmC) in UFs. High levels of 5hmC upregulate tet methylcytosine dioxygenase 1 (TET1) or tet methylcytosine dioxygenase 3 (TET3) mRNA and protein expression, resulting in UFs cell proliferation. Genetic disruption affecting monocytic leukemia zinc finger protein-related factor (MORF) results in the distinct gene expression pattern of LM pathogenesis.30


When diagnosing UFs, the first option would be ultrasonography, which can be done as abdominal or vaginal ultrasound, with transvaginal ultrasound being the golden standard thanks to its high specificity and sensitivity in UFs detection. Other more advanced imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, can be used if the ultrasound is inconclusive.31

The technological advancement in imaging has made “fibroid mapping,” which can be defined as an accurate description of the location, size, and characteristics of UFs, more precise and less invasive. Ultrasonography can help characterize submucous myomas and determine the closeness of intramural UFs to the endometrial cavity, while three-dimensional ultrasound can reconstruct the uterus’ coronal plane. On the other hand, MRI can help determine the size, vascularization, and number of UFs, their boundaries with normal myometrium, and differentiation from other pathologies like adenomyosis.31 These techniques are essential as an accurate description of the UFs is needed for successful planning of surgical treatment and complication prevention.32,33


Some clinical appearances of UFs were attributed to their contributing factors in Table 2.

Table 2: Correlation between genetics of UFs and their clinical appearance on ultrasound
Clinical appearance on imaging Genetic/epigenetic contributing factor
Hysterosalpingography findings show enlarged, elongated, displaced, distorted, or rotated uterine cavities caused by UFs34 The expression profile of miRNAs in UFs is attributed to asymmetry and deformation of the uterine cavity caused by its distortion in different directions35
The appearance of solitary tumors on ultrasound MED12 gene mutations occur twice as often as in solitary tumors19
The appearance of multiple tumors on ultrasound COMT Val/Val genotype frequency is twice as high as among patients with solitary UF19
Large fibroids (3.0 cm and over) on ultrasound36 HMGA2 fibroids tend to be larger, with an increased growth rate and higher vessel density37 UF size can be affected by the activity of ACP1 and PTPN22 genes, especially in young women38
Fibroid size appears to be very small (0.5–0.9 cm) or small (1.0–1.9 cm)36 MED12 fibroids are typically smaller and subserosal37


The incidence of UFs/LMs has been increasing substantially. Unfortunately, the symptoms of UFs are unclear, and treating UFs can include surgical intervention. It is crucial to develop effective diagnostic tools for the early detection of UFs to decrease the need for extensive interventions such as hysterectomy, myomectomy, and embolization. Therefore, thorough knowledge of the genetic and epigenetic factors affecting the pathogenesis of UFs would greatly benefit the management and treatment of UFs. This review is an effort to demystify the genetic and epigenetic interplay resulting in UF and the clinical manifestation of these factors on imaging results.


Hisham Arab


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