Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors
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Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. / Grabowski, Patricia; Schrader, Jörg; Wagner, Julia; Hörsch, Dieter; Arnold, Rudolf; Arnold, Christian N; Georgieva, Inna; Stein, Harald; Zeitz, Martin; Daniel, Peter T; Sturm, Isrid.
in: CLIN CANCER RES, Jahrgang 14, Nr. 22, 15.11.2008, S. 7378-84.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors
AU - Grabowski, Patricia
AU - Schrader, Jörg
AU - Wagner, Julia
AU - Hörsch, Dieter
AU - Arnold, Rudolf
AU - Arnold, Christian N
AU - Georgieva, Inna
AU - Stein, Harald
AU - Zeitz, Martin
AU - Daniel, Peter T
AU - Sturm, Isrid
PY - 2008/11/15
Y1 - 2008/11/15
N2 - PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified by the WHO, yet its prognostic value needs to be confirmed. Therefore, we aimed to determine the prognostic role of cell cycle key regulatory genes p53, p27kip1 (p27), and cyclin E in this tumor entity.EXPERIMENTAL DESIGN: Tumor specimen from 89 patients with a complete follow-up were studied immunohistochemically for p27 and cyclin E expression and for p53 mutations. The functional relevance of p27 was evaluated in the neuroendocrine cell lines BON1 (human) and INS1 (rat) by the use of small interfering RNA.RESULTS: Twenty-six of 29 benign, well-differentiated endocrine tumors (WHO class 1) showed a high expression (> 50%) of p27, whereas all 10 poorly differentiated endocrine carcinomas (WHO class 3) displayed a low expression of p27. Metastatic well-differentiated endocrine carcinomas (WHO class 2) showed a low p27 expression in 20 of 50 (40%) patients, which conferred a poor prognosis (median survival, 57 versus 140 months; P = 0.037). This prognostic dichotomy was improved by the use of a combination of p27 and cyclin E (high cyclin E/low p27 versus low cyclin E/high p27: median survival 53 months versus not reached; P = 0.0044). p53 mutations were rare (1 of 10 poorly differentiated endocrine carcinomas).CONCLUSIONS: Loss of p27 and overexpression of cyclin E play a critical role in the aggressiveness of gastroenteropancreatic neuroendocrine tumors. This coincides with increased cell cycle progression. We propose a discussion whether to incorporate the immunohistochemical expression of p27 into a revised classification to individualize therapeutic strategies in this tumor entity.
AB - PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified by the WHO, yet its prognostic value needs to be confirmed. Therefore, we aimed to determine the prognostic role of cell cycle key regulatory genes p53, p27kip1 (p27), and cyclin E in this tumor entity.EXPERIMENTAL DESIGN: Tumor specimen from 89 patients with a complete follow-up were studied immunohistochemically for p27 and cyclin E expression and for p53 mutations. The functional relevance of p27 was evaluated in the neuroendocrine cell lines BON1 (human) and INS1 (rat) by the use of small interfering RNA.RESULTS: Twenty-six of 29 benign, well-differentiated endocrine tumors (WHO class 1) showed a high expression (> 50%) of p27, whereas all 10 poorly differentiated endocrine carcinomas (WHO class 3) displayed a low expression of p27. Metastatic well-differentiated endocrine carcinomas (WHO class 2) showed a low p27 expression in 20 of 50 (40%) patients, which conferred a poor prognosis (median survival, 57 versus 140 months; P = 0.037). This prognostic dichotomy was improved by the use of a combination of p27 and cyclin E (high cyclin E/low p27 versus low cyclin E/high p27: median survival 53 months versus not reached; P = 0.0044). p53 mutations were rare (1 of 10 poorly differentiated endocrine carcinomas).CONCLUSIONS: Loss of p27 and overexpression of cyclin E play a critical role in the aggressiveness of gastroenteropancreatic neuroendocrine tumors. This coincides with increased cell cycle progression. We propose a discussion whether to incorporate the immunohistochemical expression of p27 into a revised classification to individualize therapeutic strategies in this tumor entity.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Animals
KW - Blotting, Western
KW - Cell Nucleus
KW - Cyclin E
KW - Cyclin-Dependent Kinase Inhibitor p27
KW - Digestive System Neoplasms
KW - Female
KW - Humans
KW - Immunohistochemistry
KW - Kaplan-Meier Estimate
KW - Male
KW - Middle Aged
KW - Mutation
KW - Neuroendocrine Tumors
KW - Oncogene Proteins
KW - Polymerase Chain Reaction
KW - Polymorphism, Single-Stranded Conformational
KW - Prognosis
KW - Rats
KW - Tumor Markers, Biological
KW - Tumor Suppressor Protein p53
U2 - 10.1158/1078-0432.CCR-08-0698
DO - 10.1158/1078-0432.CCR-08-0698
M3 - SCORING: Journal article
C2 - 19010853
VL - 14
SP - 7378
EP - 7384
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 22
ER -