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Uterine Fibroid Meta-Analysis Leads to Loci Involved in Tumor, Hormone-Related Conditions

NEW YORK (GenomeWeb) – At least some of the genetic loci that confer enhanced risk of uterine leiomyomas — commonly known as uterine fibroids — seem to contribute to other hormone-related traits or tumor conditions, according to a new meta-analysis by researchers from Decode Genetics/Amgen, the University of Iceland, and other centers.

Using genotyping data for nearly 540,000 women with or without the benign uterine smooth muscle tumors, the team tracked down 21 leiomyoma-associated variants falling at 16 sites in the genome. As they described online today in Nature Communications, when they dug into these sites further, the investigators saw overlaps between several leiomyoma-linked loci and those implicated in conditions such as endometriosis, breast cancer, malignant tumor risk, or risk of benign tumors.

"Results from this meta-analysis highlight two distinct genetic pathways that play a role in the development of leiomyomas; one of genes linked to tumorigenesis (TP53, TERT, ATM, and OBFC1) and the other of variants and loci linked to hormone metabolism (CDC42/WNT4, GREB1, MCM8, and SYN/ESR1)," senior and co-corresponding author Kari Stefansson, Decode's CEO and a University of Iceland researcher, and his co-authors wrote.

Moreover, the team noted that a polygenic risk score developed for leiomyoma using data from the UK Biobank project also showed significant ties to thyroid cancer, prostate cancer, and overall cancer risk in individuals in Iceland. Together, the findings "show a genetic overlap between leiomyoma and various cancers, and highlight the role of estrogen in tumor growth," Stefansson and his co-authors concluded.

Past studies have suggested that leiomyoma tumors respond to estrogen, the team noted, and the majority of African-American and Caucasian women develop the tumors by the time they reach 50 or older. But despite being benign, the pelvic tumors can cause a wide range of medical issues, from pain and bleeding to infertility or pregnancy complications that lead to cesarean section surgery. 

In an effort to better understand genetic contributors to leiomyoma formation, Stefansson and his colleagues considered Illumina or Affymetrix genotyping array data for 16,595 hospital-based leiomyoma cases and 523,330 unaffected controls, enrolled from the Icelandic population or from the UK Biobank project.

In the Icelandic participants, including 6,728 individuals with leiomyoma and 124,542 without, whole-genome sequence data for more than 15,000 Icelanders were used for imputation and long-range variant phasing. Imputation in the 408,655 UK Biobank cases and controls was done at the Wellcome Trust Centre for Human Genetics using data from the Haplotype Reference Consortium and the UK10K project.

The team's meta-analysis initially led to 412 variants at 16 loci, with five more loci turning up after conditional analyses — a set it whittled down to 19 variants with genome-wide significant, independent leiomyoma associations and two secondary variants at 21 loci.

Through a series of follow-up analyses, the researchers explored the genes, pathways, and regulatory regions most apt to be affected by these variants, while searching for additional conditions influenced by the same SNPs or loci. Along with leiomyoma-associated variants falling in cancer-related genes such as ATM, for example, they found that a variant involved in risk of the benign tumors influenced expression of TP53.

Based on the overlap identified with tumor- and hormone-related pathways, the authors wrote, "It is tempting to speculate that the tumor-associated variants provide [a] genetic background for leiomyoma development, whereas the hormone-associated variants enhance the growth of the tumors, causing them to become symptomatic."