Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines

  • Akihiro Ohmoto
  • Chigusa Morizane
  • Emi Kubo
  • Erina Takai
  • Hiroko Hosoi
  • Yasunari Sakamoto
  • Shunsuke Kondo
  • Hideki Ueno
  • Kazuaki Shimada
  • Shinichi Yachida
  • Takuji Okusaka
Original Article—Liver, Pancreas, and Biliary Tract



Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population.


Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases.


The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants.


These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.


Pancreatic cancer Lynch syndrome DNA mismatch repair genes Revised Bethesda guidelines Germline variants 



We wish to thank all of the patients and their families who contributed to this study. We also thank Dr. Kokichi Sugano and Dr. Teruhiko Yoshida (Department of Genetic Medicine and Services, National Cancer Center Hospital).


This work was supported by the National Cancer Center Research and Development Fund (28-A-1 to S.Y. and C.M.), the Takeda Science Foundation (to S.Y.), and the Pancreas Research Foundation of Japan (to A.O.). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan.

Compliance with ethical standards

Conflict of interest

All the authors declare no potential conflicts of interest.

Supplementary material

535_2018_1466_MOESM1_ESM.xlsx (17 kb)
Supplementary material 1 (XLSX 16 kb)


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Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Akihiro Ohmoto
    • 1
  • Chigusa Morizane
    • 2
  • Emi Kubo
    • 2
  • Erina Takai
    • 1
  • Hiroko Hosoi
    • 2
  • Yasunari Sakamoto
    • 2
  • Shunsuke Kondo
    • 2
  • Hideki Ueno
    • 2
  • Kazuaki Shimada
    • 3
  • Shinichi Yachida
    • 1
    • 4
  • Takuji Okusaka
    • 2
  1. 1.Laboratory of Clinical GenomicsNational Cancer Center Research InstituteTokyoJapan
  2. 2.Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center HospitalTokyoJapan
  3. 3.Department of Hepatobiliary and Pancreatic SurgeryNational Cancer Center HospitalTokyoJapan
  4. 4.Department of Cancer Genome Informatics, Graduate School of Medicine/Faculty of MedicineOsaka UniversityOsakaJapan

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