Morphomolecular characterisation of NET G3 during metastatic progression

• Applicant: Dr. Atsuko Kasajima
• Subject Area: Pathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516741100

Neuroendocrine tumor (NET) G3 is defined as a highly proliferative tumor group with a Ki67 index of >20%. We analyzed in different organs in 1513 NEN cases and found that NET G3 occur with variable frequency in different organs, 42% in pancreas , followed by stomach and ileum. Extremely rarely affected are esophagus, duodenum, jejunum, appendix, colon, and rectum. NETs G3 do not express p53 or Rb1 in more than 90% of cases and thus clearly differ from neuroendocrine carcinomas (NECs) in its molecular biology, although they are similar in outcome. As a next step, we investigated the clinical course of the NETs G3 and have recognized that most NETs G3 have synchronous liver metastases at first diagnosis ("de-novo" NET G3) but a part of the NETs G3 evolves from NET G1/G2 ("transit" NET G3). In some of these NETs G3, p53 mutations were detected in the time course. Of the 70 NET G3 with known progression course, 54 (77%) were identified as "de-novo" and 16 (23%) as "transit" NET G3. The difference between Ki67 indices in a progressing NET G3 (delta Ki67 value) is higher in "transit" NETs G3 than in "de-novo" NET G3. The highest delta Ki67 value was found in three pancreatic and one rectal NET G3, all of which showed strong overexpression of p53 in the liver metastasis, indicating a mutation in the TP53 gene. Based on these initial data, we hypothesize that aggressive metastatic progression of NETs G3 is primarily associated with p53 mutations in tumor tissue. The factors involved in gradual or rapid progression from NET G1/G2 to NET G3, as well as the mechanism of “de novo” development of NET G3, remain unclear and are the subject of research. The overall goal of this research project is to morphomolecularly characterize NETs G3 during the metastatic progression. The specific goals are; 1) Clarify the origin and metastatic progression of NET G3. 2) Characterize molecular changes of NET G3 during metastatic progression. 3) Morphomolecular comparison of rapid-progressive with slow-progressive NET G3.

• DFG Programme: Research Grants