Study Identifies Molecular Mechanisms of Uterine Leiomyomas

New data demonstrated that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. Based on the results, an accurate molecular classification of uterine leiomyomas is emerging. Identifying the potential mechanisms that cause leiomyomas may help in the development of targeted therapies against these lesions, according to findings published online in the New England Journal of Medicine [doi:10.1056/NEJMoa1302736].

Uterine leiomyomas are benign tumors that affect up to 77% of women in the United States of reproductive age. Although leiomyomas are believed to be chromosomally rather stable, approximately 40% to 50% of leiomyomas have detectable cytogenetic rearrangements such as deletions of 7q and rearrangements involving 12q15 or 6p21. HMGA2 is the driver gene for tumors carrying 12q15 rearrangements. Along with chromosomal changes, point mutations in MED12 contribute to the development of leiomyomas.

Because a better understanding of the molecular mechanisms is still lacking and may provide clues to the prevention and treatment of these lesions, researchers analyzed samples of uterine leiomyomas that were positive for a MED12 mutation, were deficient in fumarate hydratase (FH), or lacked MED12 and FH mutations. All normal and tumor tissues were examined histopathologically. The investigators performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium tissue from 30 women.

The samples were collected between 2001 and 2008 at the Helsinki University Central Hospital, Helsinki, Finland, at hysterectomy and frozen while fresh. The leiomyomas were selected to include 16 that were positive for a MED12 mutation, 4 that were deficient in FH, and 18 that lacked MED12 and FH mutations. A genome-wide analysis of all tumors for somatic structural variations, copy-number alterations, point mutations, and insertions or deletions was performed.

Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. The results found that 2 tumors in 1 patient, 2 tumors in a second patient, and 5 tumors in a third patient were shown to have a common clonal origin. All 9 tumors represented the leiomyoma subclass that overexpresses HMGA2. The researchers also observed interconnected complex chromosomal rearrangements (CCRs) resembling chromothripsis in 3 of the 16 MED12-mutated tumors, 0 of the 4 FH-deficient tumors, and 12 of the 16 tumors lacking MED12 and FH mutations. Previous studies have found that chromothripsis has been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a part in the genesis and progression of benign tumors.

A CCR event was defined as a series of rearrangements with a minimum of 3 double-strand breaks involving 6 DNA ends. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma. Some uterine leiomyomas had multiple independent CCR events. One event involved chromosomes 1, 2, and 20, and another involved chromosomes 12 and 14, resulting in a RAD51B-HMGA2 rearrangement.

The findings also showed that alterations in the COL4A5 and COL4A6 locus recurred in uterine leiomyomas and also arose through chromothripsis. Analysis of the transcriptome-wide differential expression revealed IRS4, located next to COL4A5, was found to be the 15th most differentially expressed gene (P=.02 after adjustment for the false discovery rate) in 3 samples with these alterations. In these 3 tumors, the level of differential expression was on average 5.6 times as high as in the 65 arrayed samples without the alterations.