Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors.
OBJECTIVE
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.


METHODS
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.
Grabowski
Patricia
P
Medizinische Klinik I, Gastroenterologie/Infektiologie/Rheumatologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. patricia.grabowski@charite.de
Schrader
Jörg
J
Wagner
Julia
J
Hörsch
Dieter
D
Arnold
Rudolf
R
Arnold
Christian N
CN
Georgieva
Inna
I
Stein
Harald
H
Zeitz
Martin
M
Daniel
Peter T
PT
Sturm
Isrid
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D019927:Cyclin E / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D004067:Digestive System Neoplasms / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27