Leiomyoma, commonly referred to as uterine fibroids, are common growths that affect a large percentage of women globally. The presence of these tumors often raises questions about their underlying cause, particularly whether they represent a genetic disorder passed down through families. While family history influences risk, the relationship between leiomyoma and genetics is complex, involving specific cellular changes that usually occur only within the tumor itself. Understanding this distinction is important for clarifying the origin of fibroids and the implications for inheritance risk.
Understanding Uterine Leiomyoma
Uterine leiomyomas are benign tumors that develop from the smooth muscle cells of the uterus, specifically within the myometrium layer. They are the most frequently diagnosed pelvic tumor in women of reproductive age, with estimates showing that 50% to 70% of women will develop them by the time they reach menopause. These growths vary significantly in size, number, and location, sometimes causing symptoms like heavy menstrual bleeding, pelvic pain, or pressure. Transformation to a malignant tumor is extremely rare, occurring in less than 0.1% of cases.
The Role of Specific Gene Mutations
The development of a leiomyoma is often linked to a specific change in the DNA of a single uterine muscle cell, leading to the formation of a monoclonal tumor. The most frequently identified genetic alteration involves the MED12 gene, which codes for a subunit of the Mediator complex, a structure that regulates gene expression. Mutations in the MED12 gene are found in approximately 45% to 85% of uterine leiomyomas, making it the primary genetic driver in most cases.
This specific mutation typically occurs in exon 2 of the gene, with a common change being a missense mutation at codon 44. The alteration to the MED12 protein disrupts the normal signaling pathways within the cell, particularly those related to the cell cycle, promoting uncontrolled growth of the mutated cell line. While MED12 mutations are the most common finding, other genetic aberrations also contribute to fibroid formation in cases where MED12 is normal.
Less common genetic drivers include the overexpression of the HMGA2 gene and deletions in the COL4A5 and COL4A6 genes. Mutations in the FH (Fumarate Hydratase) gene are also sometimes present, particularly in tumors with distinct cellular features. These diverse genetic findings highlight that leiomyomas are not a single disease but a group of tumors with different molecular origins that share a common growth pattern.
Acquired Mutation Versus Inherited Disorder
Despite the strong genetic component found in the tumors, leiomyoma is generally not classified as a classic inherited disorder. This distinction rests on the difference between somatic and germline mutations. A germline mutation is a change in the DNA that is present in the egg or sperm cells, meaning it is passed down from a parent and is present in every cell of the offspring’s body.
In contrast, the vast majority of genetic changes that drive leiomyoma are somatic mutations, which occur after conception in a single cell within the uterine wall. This means the mutation is acquired during a person’s lifetime and is confined only to the cells of the resulting tumor, not the reproductive cells. Since the mutation is not present in the reproductive cells, the specific MED12 mutation that caused a woman’s fibroid cannot be passed directly to her children.
There are rare exceptions, such as Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) syndrome, which is a true inherited genetic disorder caused by a germline mutation in the FH gene. Individuals with HLRCC have a high risk of developing multiple leiomyomas, along with other tumors, because the mutation is present in all their cells from birth.
However, this inherited form accounts for a very small fraction of all leiomyoma cases. The familial clustering observed in most cases is thought to be due to shared environmental factors or low-penetrance genetic susceptibilities, rather than the direct inheritance of the tumor-driving mutation.
Hormonal and Other Contributing Factors
The initiation of leiomyoma growth is often a genetic event, but the subsequent growth and development of the tumor are heavily influenced by non-genetic factors, particularly hormones. Both estrogen and progesterone, the primary female reproductive hormones, play a significant role in promoting the growth of established fibroids. Leiomyoma tissue expresses higher levels of receptors for both of these hormones compared to the surrounding normal uterine muscle.
The growth of fibroids is clearly linked to the presence of these hormones, which is why they typically arise during the reproductive years and often regress after menopause when hormone levels decline. Progesterone is thought to be a particularly potent promoter, acting as a survival factor for the tumor cells and increasing the production of growth factors. This hormonal dependency explains why therapies targeting these hormone pathways can sometimes reduce fibroid size and alleviate symptoms.
Beyond hormones, several demographic and lifestyle factors influence the risk of developing leiomyoma. Women of African ancestry have a significantly higher risk and often develop fibroids at a younger age and with greater severity compared to other populations. Risk factors include:
- Early age of first menstruation.
- Increased body mass index (BMI).
- Pregnancy (decreases risk).
- Use of certain hormonal contraceptives (decreases risk).