Are uterine fibroids really clonal? (#22)
All published evidence to date states that uterine fibroids are clonal in origin and derived from the expansion of a single altered smooth muscle cell (SMC). We identified 14 studies that report clonality of uterine fibroids of which only 2 used more than 20 patients, and only 1 performed quantitative data analysis. Our studies examining the cellular constituents of fibroids highlight that in addition to SMC, fibroblasts make up a second major cellular component of these tumours (up to 40% in some samples), and that fibroblasts have significantly altered morphology in fibroids compared to myometrium1. The aim of this study was to re-assess clonality of uterine fibroids. We employed the commonly used human androgen receptor assay (HUMARA). Following gDNA extraction, samples (n=60) were digested (or mock digested) with Hha1 enzyme. HUMARA PCR was performed on +/- digested samples, quantified using automated fragment analysis and the allele ratio was calculated2. Samples with an allele ratio greater than 75:25 were considered ‘clonal’. Surprisingly, out of 53 informative samples, only 24.5% demonstrated clonal fibroid and non-clonal myometrium. Most patients (49%) were identified to be non-clonal for both myometrium and fibroid. 18% of patients had non-clonal fibroids and clonal myometrium, while a small population (7.5%) were clonal for both tissues. This study provides new data to challenge the common dogma that uterine fibroids uniformly consist of clonally derived smooth muscle cells. Our findings indicate that these tumors are not derived from a single cell population, and the origin and function of other cell types such as fibroblasts are not known. We subsequently sorted myometrial and fibroid tissues into fibroblast and SMC populations (n=10). HUMARA results were highly variable between different cell types, with no distinct clonal patterns. These data warrant further investigation into the cellular origins of fibroids and possible re-classification of the literature.
- 1. Zaitseva, M., Vollenhoven, B.J., and Rogers, P.A.W. Retinoic acid pathway genes show significantly altered expression in uterine fibroids when compared with normal myometrium. Molecular Human Reproduction, 2007. 13(7-8): p. 577-585.
- 2. Lau, A.W., et al., Skewed X-Chromosome Inactivation Is Common in Fetuses or Newborns Associated with Confined Placental Mosaicism. The American Journal of Human Genetics, 1997. 61(6): p. 1353-1361.