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Exome Sequencing Study Uncovers Risk Gene for Uterine Fibroids

By Andrea Anderson

NEW YORK (GenomeWeb News) – A transcription regulating gene called MED12 is frequently mutated in a type of benign uterine tumors called uterine leiomyomas, or fibroids, according to an exome-sequencing study in the early, online version of Science today.

Researchers from Finland and Sweden used whole-exome sequencing to look for fibroid-related mutations in 18 tumor samples from 17 women. Of these, 10 harbored mutations in the X-chromosome gene called mediator complex subunit 12 (MED12). When they did follow-up screening on hundreds more fibroids, the team detected MED12 mutations in 70 percent of the samples.

"This was sort of a nice surprise that so many of these tumors seem to have this apparent driver mutation," senior author Lauri Aaltonen, a medical genetics researcher at the University of Helsinki, told GenomeWeb Daily News. "It was something that we hoped for, but in many tumor types people have not found such a key mutation."

Roughly 60 percent of women get uterine fibroids by the time they are 45 years old, Aaltonen and co-authors explained. Half of these cases show symptoms, they noted, which can be severe in some instances, leading to infertility or hysterectomy.

A few chromosomal rearrangements have been found in uterine fibroid samples, but most of these turn up in relatively few cases overall, hinting that additional, unidentified genetic changes might also contribute to the condition.

"There are a small number of genetic changes, such as translocations, which have been described and typically these occur in not more than 15 percent of leiomyomas," Aaltonen said. "So previously one very frequent, specific mutation type has not been identified in these lesions."

The researchers used the Agilent SureSelect Human Exon kit to capture coding sequences using genomic DNA from 18 fresh frozen uterine leiomyoma and matched normal samples from 17 patients who had hysterectomy surgery at Helsinki University Central Hospital. These exomes were then sequenced using the Illumina GAII exomes.

When they analyzed this exome sequence data, the team found that 10 of the 18 fibroid samples contained mutations affecting MED12, with eight of these MED12 mutations turning up in codon 44 of the gene.

To look at this in more detail, they then used capillary sequencing on the 18 fibroid samples tested initially, along with 225 more fibroid samples from 80 individuals. Nearly half of the samples tested — 49 percent — harbored missense mutations affecting exon 44 of MED12.

Meanwhile, their additional follow-up experiments uncovered mutations in exon 2 of the gene. Overall, the team saw MED12 mutations in over 70 percent of the 225 tumors that they screened in the validation step, with three-quarters of the women having at least one fibroid sample that contained a glitch in MED12.

Together, the results hint that fibroids may be a consequence of changes to transcriptional processes affecting genes in the smooth muscle of the uterus, since MED12 is known to be parts of a large transcription-regulating complex known as the Mediator Complex, which helps bring together regulatory sequences on DNA with RNA Pol II initiator proteins.

"The Mediator Complex is believed to have roles in general as well as gene-specific transcription," the study authors noted. "We speculate that the tumorigenic effect of the mutations in uterine smooth muscle but not in other tissue types may relate to the latter."

"[T]he discovery of frequent MED12 mutations in uterine leiomyomas should fuel further work to elucidate the role of this protein, and the Mediator Complex in general, in both normal cell biology and tumorigenesis," they added.

Indeed, when they did gene expression analyses on a subset of the MED12 mutation-containing tumors and matched normal samples with the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, the researchers found shifts in the expression of genes from focal adhesion, Wnt signaling, and extracellular matrix receptor-related pathways.

The team is doing a variety of follow-up studies aimed at trying to understand the functional implications of MED12 mutations and their role in fibroid development, Aaltonen said. They are also keen to learn more about whether these mutations characterize a specific uterine leiomyoma sub-type.

"Certainly we can say that this finding is a very good step forward in the molecular classification of leiomyomas and we really should be learning a lot of new things in the near future," Aaltonen said.

In the long term, the researchers are optimistic that the newly identified mutations might serve as targets for treating at least some fibroids, he added, particularly since the MED12 mutations appear to occur quite frequently but are concentrated in relatively few parts of the gene.

"If you think about targeted therapy as a long term goal for this type of research, this type of [frequent, specific mutation pattern] is, of course, much more favorable than if you had various mutations here and there," he said. "If that happens, it's going to take a long time, of course, but it's a good starting point."

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