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APOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis

Journal of Human Genetics volume 67, pages 323–329 (2022)Cite this article

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Abstract

Endometriosis is a benign gynecologic condition, acting as a precursor of certain histological subtypes of ovarian cancers. The epithelial cells of endometriotic tissues and normal uterine endometrium accumulated somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Kirsten rat sarcoma (KRAS) proto-oncogene. To determine the genomic characteristic of endometriotic epithelial cells and normal uterine endometrium and to identify the predominant mutational process acting on them, we studied the somatic mutation profiles obtained from whole exome sequencing of 14 endometriotic epithelium and 11 normal uterine endometrium tissues and classified them into mutational signatures. We observed that single base substitutions 2/13 (SBS), attributed to Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit (APOBEC) induced mutagenesis, were significant in endometriotic tissues, but not in the normal uterine endometrium. Additionally, the larger number and wider allele frequency distribution of APOBEC signature mutations, compared to cancer-associated driver mutations in endometriotic epithelium suggested APOBEC mutagenesis as an important source of mutational burden and heterogeneity in endometriosis. Further, the relative risk of enriched APOBEC signature mutations was higher in endometriosis patients who were carriers of APOBEC3A/3B germline deletion, a common polymorphism in East Asians which involves the complete loss of APOBEC3B coding region. Our results illustrate the significance of APOBEC induced mutagenesis in driving the genomic heterogeneity of endometriosis.

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Acknowledgements

We are grateful to Junko Kajiwara, Junko Kitayama, Yumiko Sato and Anna Ishida for their technical assistances.

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Authors and Affiliations

  1. Human Genetics Laboratory, National Institute of Genetics, Mishima, 411-8540, Japan

    Sundaramoorthy Revathidevi, Hirofumi Nakaoka, Naoko Fujito & Ituro Inoue

  2. Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Chiyoda-ku, 101-0062, Japan

    Hirofumi Nakaoka

  3. Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan

    Kazuaki Suda, Kosuke Yoshihara & Takayuki Enomoto

  4. Department of Genetics, Dr ALM PG IBMS, University of Madras, Chennai, 600113, India

    Arasambattu Kannan Munirajan

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Correspondence to Hirofumi Nakaoka or Ituro Inoue.

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Revathidevi, S., Nakaoka, H., Suda, K. et al. APOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis. J Hum Genet 67, 323–329 (2022). https://doi.org/10.1038/s10038-021-01003-y

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