Abstract 5126: Genetic analysis of metachronous pancreatic cancers
Authors: Tomonori Hirano , Kakiuchi Nobuyuki , Takeuchi Yasuhide , Inoue Yoshikage , Nishimura Tomomi , Fujii Yoichi , Yokoyama Akira , Makishima Hideki , Masui Toshihiko , Uemoto Shinji , Minamiguchi Sachiko , Haga Hironori , Chiba Kenichi , Tanaka Hiroko , Shiraishi Yuichi , Miyano Satoru , Uza Norimitsu , Kodama Yuzo , Seno Hiroshi , Chiba Tsutomu , Ogawa Seishi 
Published: August 2019

[Introduction] Early detection of pancreatic cancer is a key to curable surgery, although many are diagnosed in advanced stage. However, even in those cases in which cancer was detected early enough for curative resection, metachronous pancreatic cancer may occur in residual pancreas, whose pathogenesis, including its relationship with primary cancer, has been poorly understood. In this study, we aimed to reveal the origin of metachronous pancreatic cancers using an unbiased detection of somatic mutations in primary and metachronous cancers as well as adjacent precursor lesions.

[Methods] Samples were obtained from longitudinal sampling from above lesions using laser microdissection from formalin-fixed paraffin-embedded surgical specimens. DNA was extracted and analyzed for somatic mutations of each lesion by whole-exome sequencing with matched normal DNA. On the basis of shared and private mutations across different samples, we interrogated history of clonal evolution of these lesions.

[Results] Four patients were enrolled who underwent curative surgery for early pancreatic cancer and subsequently for metachronous tumors in the residual pancreas. Pathology from surgery for primary cancer were margin-negative in all patients. The median interval between the initial and second surgery was 29.8 months (22.8 - 38.3 months). The number of precursor lesions analyzed was from 0 to 5 per patient. The median number of somatic mutations per sample was 78 (range: 41-92) in cancers and 20 (14-42) in precursor lesions. None of the patients have known pathogenic germline mutations. With a median of 78 and 20 mutations per sample, all samples had one or more driver mutations. In each case, all driver mutations that were detected in cancers were shared between primary and metachronous cancer. It indicated that metachronous cancer branched off from primary cancers at later stage of carcinogenesis. And negative margin at initial surgery suggested that metachronous cancer was formed by dissemination or metastasizing rather than Intraductal progression. By contrast, none of the mutations other than a hotspot KRAS mutations were shared between precursor lesions and cancers, suggesting multiple independent clonal growth of precancerous cells in the cancer bearing pancreas.

[Conclusions] Our study shows that metachronous pancreatic cancers are derived from the same origin of initial cancer. Therefore, even in the case of early pancreatic cancer careful checkup for recurrence in the residual pancreas is important.

Citation Format: Hirano Tomonori, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Yoshikage Inoue, Tomomi Nishimura, Yoichi Fujii, Akira Yokoyama, Hideki Makishima, Toshihiko Masui, Shinji Uemoto, Sachiko Minamiguchi, Hironori Haga, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Norimitsu Uza, Yuzo Kodama, Hiroshi Seno, Tsutomu Chiba, Seishi Ogawa. Genetic analysis of metachronous pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5126.