Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

Niko Välimäki(University of Helsinki), Heli Kuisma(University of Helsinki), Annukka Pasanen(University of Helsinki), Oskari Heikinheimo(University of Helsinki), Jari Sjöberg(University of Helsinki), Ralf Bützow(University of Helsinki), Nanna Sarvilinna(University of Helsinki), Hanna-Riikka Heinonen(University of Helsinki), Jaana Tolvanen(University of Helsinki), Simona Bramante(University of Helsinki), Tomas Tanskanen(University of Helsinki), Juha Auvinen(University of Oulu), Outi Uimari(Oulu University Hospital), Amjad Alkodsi(University of Helsinki), Rainer Lehtonen(University of Helsinki), Eevi Kaasinen(University of Helsinki), Kimmo Palin(University of Helsinki), Lauri A. Aaltonen(University of Helsinki)
eLife
September 18, 2018
10.7554/elife.37110
Cited by 89Open Access
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Abstract

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

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