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

Patricia Grabowski; Jörg Schrader; Julia Wagner; Dieter Hörsch; Rudolf Arnold; Christian N Arnold; Inna Georgieva; Harald Stein; Martin Zeitz; Peter T Daniel; Isrid Sturm

doi:10.1158/1078-0432.CCR-08-0698

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

Standard

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, Vol. 14, No. 22, 15.11.2008, p. 7378-84.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Grabowski, P, Schrader, J, Wagner, J, Hörsch, D, Arnold, R, Arnold, CN, Georgieva, I, Stein, H, Zeitz, M, Daniel, PT & Sturm, I 2008, 'Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors', CLIN CANCER RES, vol. 14, no. 22, pp. 7378-84. https://doi.org/10.1158/1078-0432.CCR-08-0698

APA

Grabowski, P., Schrader, J., Wagner, J., Hörsch, D., Arnold, R., Arnold, C. N., Georgieva, I., Stein, H., Zeitz, M., Daniel, P. T., & Sturm, I. (2008). Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. CLIN CANCER RES, 14(22), 7378-84. https://doi.org/10.1158/1078-0432.CCR-08-0698

Vancouver

Grabowski P, Schrader J, Wagner J, Hörsch D, Arnold R, Arnold CN et al. Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. CLIN CANCER RES. 2008 Nov 15;14(22):7378-84. https://doi.org/10.1158/1078-0432.CCR-08-0698

Bibtex

@article{86b17ecd0eb34d88917ff3561fba3463,

title = "Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors",

abstract = "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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Animals, Blotting, Western, Cell Nucleus, Cyclin E, Cyclin-Dependent Kinase Inhibitor p27, Digestive System Neoplasms, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Neuroendocrine Tumors, Oncogene Proteins, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Prognosis, Rats, Tumor Markers, Biological, Tumor Suppressor Protein p53",

author = "Patricia Grabowski and J{\"o}rg Schrader and Julia Wagner and Dieter H{\"o}rsch and Rudolf Arnold and Arnold, {Christian N} and Inna Georgieva and Harald Stein and Martin Zeitz and Daniel, {Peter T} and Isrid Sturm",

year = "2008",

month = nov,

day = "15",

doi = "10.1158/1078-0432.CCR-08-0698",

language = "English",

volume = "14",

pages = "7378--84",

journal = "CLIN CANCER RES",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "22",

}

RIS

TY - JOUR

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 -