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How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression

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Abstract

Intestinal-type intraductal papillary mucinous neoplasm (IPMN) of the pancreas is clinicopathologically distinctive. Our research aimed to elucidate the molecular mechanism of the development and progression of the intestinal-type IPMN. In 60 intestinal-type IPMN specimens, histological transitions from gastric-type epithelia to intestinal-type epithelia were observed in 48 cases (80%). CDX2/MUC2/alcian blue triple staining indicated that CDX2 appeared to precede MUC2 expression and subsequent alcian blue-positive mucin production. Expression of p21 and Ki-67 seemed to be accelerated by CDX2 expression (p = 6.02e-13 and p = 3.1e-09, respectively). p21/Ki-67 double staining revealed that p21 was mostly expressed in differentiated cells in the apex of papillae, while Ki-67 was expressed in proliferative cells in the base of papillae. This clear cellular arrangement seemed to break down with the progression of atypical grade and development of invasion (p = 0.00197). Intestinal-type IPMNs harbored frequent GNAS mutations (100%, 25/25) and RNF43 mutations (57%, 8/14) and shared identical GNAS and KRAS mutations with concurrent gastric-type IPMNs or incipient gastric-type neoplasia (100%, 25/25). RNF43 mutations showed emerging or being selected in intestinal-type neoplasms along with ß-catenin aberration. Activation of protein kinase A and extracellular-regulated kinase was observed in CDX2-positive intestinal-type neoplasm. These results suggest that gastric-type epithelia that acquire GNAS mutations together with induction of intrinsic CDX2 expression may evolve with clonal selection and additional molecular aberrations including RNF43 and ß-catenin into intestinal-type IPMNs, which may further progress with complex villous growth due to disoriented cell cycle regulation, acceleration of atypical grade, and advance to show an invasive phenotype.

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Acknowledgments

We would like to thank Ms. Fumiko Date (Biomedical Research Core of Tohoku University Graduate School of Medicine) for tissue sample preparation, and Ms. Yuko Hayakawa (Sapporo Higashi Tokushukai Hospital) for technical support in the genetic analysis. The authors would also like to thank Mr. David Hochman for the editorial review of the manuscript.

Funding

This work was supported by the Japan Society for the Promotion of Science, KAKENHI Grant Number JP19K16576 (to Y. Omori).

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Authors and Affiliations

  1. Department of Investigative Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai, 980-8575, Japan

    Yuko Omori, Toshikazu Kobayashi & Toru Furukawa

  2. Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, 065-0033, Japan

    Yusuke Ono, Hidenori Karasaki & Yusuke Mizukami

  3. Department of Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan

    Yusuke Ono & Yusuke Mizukami

  4. Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan

    Toshikazu Kobayashi, Naohiko Makino & Yoshiyuki Ueno

  5. Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Fuyuhiko Motoi & Michiaki Unno

Authors
  1. Yuko Omori
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  2. Yusuke Ono
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  10. Toru Furukawa
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Contributions

Y. Omori and T.F. performed the histological analysis; Y. Omori performed the immunohistochemical analysis; Y. Omori and Y. Ono performed genetic analysis and Y. Omori interpreted the data; T.K., F.M., and M.U. collected clinical samples; Y. Omori obtained the funding; Y.M., H.K., N.M., Y.U., and T.F. supervised the project; Y. Omori developed the concept, designed experimental studies, analyzed the data, and wrote the manuscript with feedback from all authors. T.F. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Toru Furukawa.

Ethics declarations

This study was approved by the Institutional Review Board of Tohoku University, Graduated School of Medicine (#2018-1-752).

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The authors declare that they have no conflicts of interest.

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Omori, Y., Ono, Y., Kobayashi, T. et al. How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression. Virchows Arch 477, 21–31 (2020). https://doi.org/10.1007/s00428-020-02806-8

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