Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes
Keijiro Mizukami,
Yusuke Iwasaki,
Eiryo Kawakami,
Makoto Hirata,
Yoichiro Kamatani,
Koichi Matsuda,
Mikiko Endo,
Kokichi Sugano,
Teruhiko Yoshida,
Yoshinori Murakami,
Hidewaki Nakagawa,
Amanda B. Spurdle,
Yukihide Momozawa
Affiliations
Keijiro Mizukami
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
Yusuke Iwasaki
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
Eiryo Kawakami
Medical Sciences Innovation Hub Program, RIKEN, Yokohama, Kanagawa, Japan; Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
Makoto Hirata
Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo Japan
Yoichiro Kamatani
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Koichi Matsuda
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Mikiko Endo
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
Kokichi Sugano
Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo Japan; Division of Cancer Prevention and Genetic Counseling, Genome Center, Tochigi Cancer Center, Japan
Teruhiko Yoshida
Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo Japan
Yoshinori Murakami
Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Hidewaki Nakagawa
Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Amanda B. Spurdle
Division of Genetics and Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Yukihide Momozawa
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Corresponding author.
Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable. Funding: AMED under Grant Number JP19kk0305010 and Australian National Health and Medical Research funding (ID177524)
