Rb and p16 expression characterizes two subgroups of gastrointestinal poorly differentiated endocrine carcinomas with different genetic alterations.

S Pizzi, PhD, T D'Adda, BScD, C Azzoni, PhD, D Bassi, L Bottarelli, BScD, M Milione, MD, C Bordi, MD

Department of Pathology & Laboratory Medicine - Pathologic Anatomy, University of Parma, Italy.

AIM: Information on the molecular pathogenesis of highly aggressive, poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI-PDECs) is scanty. An origin in common with non-endocrine adenocarcinomas or an endocrine-like genetic pathway similar to that of well differentiated endocrine tumors have both been postulated. To clarify this issue, a systematic analysis of genes frequently altered in either endocrine or non endocrine epithelial tumors was performed on GI-PDECs. METHODS: Formalin-fixed, paraffin-embedded samples from 17 GI-PDECs were analyzed for LOH at the following loci: 3p14.2/FHIT (D3S1481), 3p21.3 (D3S1478), 11q13/MEN1 (PYGM, D11S4946, D11S913), 17p13.1/p53 (TP53.PCR15) and 18q23/DCC (D18S61). Immunohistochemical expression of FHIT, p53, Rb and p16 was also investigated. RESULTS: The following LOH rates were determined: 3p14.2, 38%; 3p21.3, 36%; 11q13, 43%; 17p13.1, 100%; 18q23, 54%. FHIT and p53 expression was altered in 23% and 68% of cases, respectively. Rb and p16 were inversely altered in 88% of GI-PDECs. P16-negative tumors showed LOH frequency at 11q13 higher than Rb-negative cases (60% vs 14%), conversely Rb-negative PDECs showed higher rates of 18q LOH (67% vs 40%). CONCLUSIONS: All GI-PDECs share p53 inactivation, distinguishing these neoplasia from well differentiated endocrine tumors. Additionally, GI-PDECs may originate through two distinct alterations of the p16-cyclinD1-CDK4-Rb pathway: 1) p16 inactivation, as seen in non-endocrine colonic carcinomas, with accompanying MEN-1 gene deletion; 2) Rb inactivation, a mechanism already found in endocrine carcinomas of the lung and causing the development of multiple endocrine tumors in Rb defective mice. GI-PDECs, therefore, encompass two subpopulations, with potential differences in prognosis and therapeutic response.

KEY WORDS: p53, endocrine tumors.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.