Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability-Reference-Cited by-同舟云学术

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

Published:2018-09-18 Issue: Volume:7 Page:
ISSN:2050-084X
Container-title:eLife
language:en
Short-container-title:

Author:

Välimäki Niko¹²^ORCID,Kuisma Heli¹²,Pasanen Annukka³^ORCID,Heikinheimo Oskari⁴,Sjöberg Jari⁴,Bützow Ralf³,Sarvilinna Nanna¹²⁴⁵,Heinonen Hanna-Riikka¹²,Tolvanen Jaana¹²^ORCID,Bramante Simona¹²,Tanskanen Tomas¹²,Auvinen Juha⁶⁷,Uimari Outi⁸,Alkodsi Amjad¹²^ORCID,Lehtonen Rainer¹²,Kaasinen Eevi¹²⁹,Palin Kimmo¹²^ORCID,Aaltonen Lauri A¹²^ORCID

Affiliation:

1. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland

2. Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland

3. Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

4. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

5. Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

6. Northern Finland Birth Cohorts' Project Center, Faculty of Medicine, University of Oulu, Oulu, Finland

7. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

8. Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland

9. Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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.

Funder

Terveyden Tutkimuksen Toimikunta

European Research Council

Syöpäjärjestöt

Sigrid Juséliuksen Säätiö

Jane ja Aatos Erkon Säätiö

Luonnontieteiden ja Tekniikan Tutkimuksen Toimikunta

NordForsk

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience