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

Niko Välimäki,Jaana Tolvanen,Hanna-Riikka Heinonen,Outi Uimari,Juha Auvinen,Simona Bramante,Ralf Bützow,Annukka Pasanen,Amjad Alkodsi,Rainer Lehtonen,Nanna Sarvilinna,Tomas Tanskanen,Jari Sjöberg,Eevi Kaasinen,Oskari Heikinheimo,Lauri A Aaltonen,Kimmo Palin,Heli Kuisma

doi:10.7554/elife.37110

Niko Välimäki, Jaana Tolvanen + Show 16 more

Open Access

https://doi.org/10.7554/elife.37110

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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.

Highlights

Uterine leiomyomas (ULs), known as fibroids or myomas, are benign smooth muscle tumors of the uterine wall
We report the most powerful Genome-wide association studies (GWAS) on uterine leiomyoma to date, and novel genome-wide significant UL susceptibility loci with plausible adjacent predisposition genes. These genes associate UL genesis to two distinct biological mechanisms: Genome stability related processes are implicated by genes Tumor Protein P53 (TP53) and ATM Serine/Threonine Kinase (ATM) together with the telomere maintenance genes Telomerase Reverse Transcriptase (TERT), Telomerase RNA Component (TERC) and STN1-CST Complex Subunit (OBFC1)
The combined UL risk of these loci was replicated in a subsequent analysis of the polygenic risk score (GRS) in six independent cohorts from different ethnic backgrounds

Summary

Introduction

Uterine leiomyomas (ULs), known as fibroids or myomas, are benign smooth muscle tumors of the uterine wall. The findings are the result of the largest genome-wide association study on fibroids, revealing a set of genes that could influence the development of fibroids Studying these genes could lead to more effective drug development to treat fibroids. We report the most powerful GWAS on uterine leiomyoma to date, and novel genome-wide significant UL susceptibility loci with plausible adjacent predisposition genes. These genes associate UL genesis to two distinct biological mechanisms: Genome stability related processes are implicated by genes Tumor Protein P53 (TP53) and ATM Serine/Threonine Kinase (ATM) together with the telomere maintenance genes Telomerase Reverse Transcriptase (TERT), Telomerase RNA Component (TERC) and STN1-CST Complex Subunit (OBFC1). We investigate the risk alleles’ association to clinical features, molecular UL subtypes, telomere length, gene expression and DNA methylation

Results

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Materials and methods

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