Pharmacogenomics and Personalized Medicine (Nov 2022)

Germline PRDM1 Variant rs2185379 in Long-Term Recurrence-Free Survivors of Advanced Ovarian Cancer

  • Mitamura T,
  • Zhai T,
  • Hatanaka KC,
  • Hatanaka Y,
  • Amano T,
  • Wang L,
  • Tanaka S,
  • Watari H

Journal volume & issue
Vol. Volume 15
pp. 977 – 984

Abstract

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Takashi Mitamura,1 Tianyue Zhai,1 Kanako C Hatanaka,2 Yutaka Hatanaka,2,3 Toraji Amano,4 Lei Wang,5,6 Shinya Tanaka,5,6 Hidemichi Watari1 1Department of Obstetrics and Gynecology, Hokkaido University Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; 2Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 3Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 4Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan; 5Institute for Chemical Reaction Design and Discovery, Hokkaido University, Sapporo, Hokkaido, Japan; 6Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, JapanCorrespondence: Takashi Mitamura, Department of Obstetrics and Gynecology, Hokkaido University Faculty of Medicine, Hokkaido University, North15, West 7, Kita-Ku, Sapporo, 0608638, Hokkaido, Japan, Tel +81 11 706 5941, Fax +81 11 706 7711, Email [email protected]: To identify the germline genetic characteristics of long-term recurrence-free survivors that can be applied to establishing a new strategy for curing advanced cancer, we investigated the whole-genome single nucleotide variants of ovarian cancer patients.Patients and Methods: DNA specimens were obtained from rare long-term recurrence-free survivors with FIGO stage III–IV ovarian cancer with no recurrence for 8– 23 years after primary treatments for a whole-genome analysis of approximately 660,000 single nucleotide variants. We then established a mouse model with a notable gene alteration by CRISPR/Cas9 to confirm the biological role.Results: The long-term recurrence-free survivors more frequently had germline heterozygous variant rs2185379 of the PRDM1 gene exon than patients with early recurrence (6.8-fold, P=0.013) and the general population. In the mouse model, primary intraperitoneal disseminated tumors of allograft ID8 were significantly smaller in the germline heterozygous rs2185379 group than in the wild-type group (57.4% decrease, P=0.008). Immunohistochemistry showed that the area of distribution of infiltrating T lymphocytes with positive CD8 staining was significantly increased in the germline heterozygous rs2185379 group in comparison to the wild-type group.Conclusion: Germline heterozygous rs2185379 in PRDM1 is correlated with an excellent prognosis and can be used to establish a new strategy for treating advanced ovarian cancer.Keywords: ovarian cancer, long-term survivors, rs2185379, PRDM1

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