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Molecular Evidence for Monoclonal Skip Progression in Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas

Date, Kenjiro MD*; Ohtsuka, Takao MD, PhD*; Fujimoto, Takaaki MD*; Tamura, Koji MD, PhD*; Kimura, Hideyo MD*; Matsunaga, Taketo MD*; Mochidome, Naoki MD; Miyazaki, Tetsuyuki MD; Mori, Yasuhisa MD, PhD*; Oda, Yoshinao MD, PhD; Nakamura, Masafumi MD, PhD*; Tanaka, Masao MD, PhD, FACS*

doi: 10.1097/SLA.0000000000001755
Original Articles

Objective: To clarify clonality of distinct multisegmental main duct (MD)-intraductal papillary mucinous neoplasms (IPMNs) using microarray analysis.

Background: IPMNs represent a pancreatic ductal cell field defect, which causes multiple occurrences of lesions. In addtion, it has been speculated that MD-IPMNs display features of monoclonal skip progression.

Methods: Total RNA was extracted from fresh-frozen tissue samples of metachronous MD-IPMNs and nonneoplastic pancreas tissue from the same pancreas from two individuals, and whole human genome microarray analysis was performed. Formalin-fixed paraffin-embedded tissue specimens from 28 distinct IPMNs were then collected from 12 patients, genomic DNA was extracted, and GNAS/KRAS mutational status was investigated. Immunohistochemical analysis was performed to validate the expression pattern of the indicated proteins.

Results: Microarray analysis revealed that metachronous MD-IPMNs from the same individual displayed pair-wise correlation coefficients of 0.9523 and 0.9512. In contrast, MD-IPMNs of the same histological grade from different individuals displayed coefficients of 0.8092 and 0.8211. Scatter plot analysis revealed that metachronous MD-IPMNs from the same individual displayed a closer linear relationship. Furthermore, heat map and hierarchical cluster analyses revealed that metachronous MD-IPMNs from the same individual were classified in the same branch, and the gene expression patterns were similar. The GNAS/KRAS mutational statuses of distinct MD-IPMNs were consistent with each other. Immunohistochemical assessment of five specific proteins demonstrated that the same expression pattern between two lesions was observed in 95% of the samples.

Conclusions: These findings using molecular analyses indicate that MD-IPMNs might display features of monoclonal skip progression.

*Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Departments of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Reprints: Takao Ohtsuka, MD, PhD, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: takao-o@surg1.med.kyushu-u.ac.jp.

Author contributions: D. K., F. T., T. K., K. H., and M. T. contributed to making the study population database and performed the data extraction, analysis, and experiments. O. T., M. Y., N. M., and T. M. contributed to the study conception and design and performed pancreatectomies and follow-up portions of the study population. M. N., M. T., and O. Y. made the pathological diagnoses. D. K. wrote the manuscript. O. T. contributed to the interpretation of results and to the manuscript revision. All authors discussed the results and commented on the manuscript. T. M. gave the final approval for this article.

This study was supported by Japan Society for Promotion of Science (JSPS) KAKENHI grant number 16H05417.

Disclosure: The authors declare no conflicts of interest.

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