About this condition
Uterine Fibroids — Genetic Risk
Uterine fibroids (leiomyomas) are the most common benign tumors in women, affecting 70-80% by age 50. Fibroids have approximately 50% heritability — first-degree relatives of affected women have 2.5x increased risk. Black women have approximately 3x higher fibroid incidence, earlier onset, and larger fibroids compared to white women — a disparity with both genetic and socioeconomic components.
MED12 somatic mutations are found in approximately 70% of fibroids, representing the most common genomic alteration. HMGA2 rearrangements cause a distinct fibroid subtype. Germline susceptibility loci identified by GWAS include variants at 10q24.33, 11p15.5, 22q13.1, and SNPs near TNRC6B, OBFC1, and BET1L. These common variants contribute to the polygenic risk that determines who develops symptomatic fibroids.
FH (fumarate hydratase) pathogenic variants cause hereditary leiomyomatosis and renal cell cancer (HLRCC) — a syndrome of aggressive uterine fibroids AND renal cell carcinoma. HLRCC fibroids are more cellular, more symptomatic, and often develop at a younger age. Identification of FH/HLRCC is critical because it triggers kidney surveillance for the associated aggressive renal cell carcinoma (collecting duct type, which requires early detection for cure).
FH-deficient fibroids (HLRCC) look different and behave aggressively — AND they come with kidney cancer risk. Any woman with early-onset, unusually symptomatic fibroids should have FH testing. Kidney surveillance could save her life.
- Gene locus
- FH (1q43), MED12 (Xq13.1), HMGA2 (12q14.3), GWAS loci (10q24.33, 11p15.5, 22q13.1)
