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

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

doi:10.7554/eLife.37110

eLife (Sep 2018)

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

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

Affiliations

Niko Välimäki: ORCiD; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Heli Kuisma: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Annukka Pasanen: ORCiD; Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Oskari Heikinheimo: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Jari Sjöberg: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Ralf Bützow: Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Nanna Sarvilinna: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
Hanna-Riikka Heinonen: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Jaana Tolvanen: ORCiD; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Simona Bramante: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Tomas Tanskanen: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Juha Auvinen: Northern Finland Birth Cohorts' Project Center, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
Outi Uimari: Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
Amjad Alkodsi: ORCiD; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Rainer Lehtonen: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Eevi Kaasinen: Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Kimmo Palin: ORCiD; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Lauri A Aaltonen: ORCiD; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland

DOI: https://doi.org/10.7554/eLife.37110
Journal volume & issue: Vol. 7

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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