Tumor Biology

, Volume 33, Issue 5, pp 1645–1651 | Cite as

Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor

  • Jae Uk Shin
  • Chang Hoon Lee
  • Kyu Taek LeeEmail author
  • Jong Kyun Lee
  • Kwang Hyuck Lee
  • Kwang Min Kim
  • Kyoung-Mee Kim
  • Sang-Mo Park
  • Jong Chul Rhee
Research Article


Ataxia telangiectasia mutated kinase (ATM) and cyclin B1 are involved in cell cycle control. The prognostic significance of both molecules has not yet been investigated in pancreatic neuroendocrine tumors. The aim of this study was to evaluate the clinical and prognostic significance of ATM and cyclin B1 in patients with pancreatic neuroendocrine tumors. A total of 107 pancreatic neuroendocrine tumor specimens that were surgically resected were immunohistochemically investigated using the tissue microarray technique. Clinicopathologic results and survival were evaluated retrospectively. High expression of ATM and cyclin B1 was related to well-differentiated endocrine tumors of the World Health Organization (WHO) classification, but not related to TNM stages. The high ATM expression group (ATM ≥ 4) had a significantly smaller tumor size, lower recurrence rate, more number of functioning tumor, and well differentiation of WHO classification. The high cyclin B1 expression group (cyclin B1 ≥5) was related to smaller tumor size, less vascular invasion, less recurrence rate, and less death rate. However, cyclin B1 was the only significant factor for survival following multivariate analysis (p = 0.008; OR, 0.54; 95 % CI, 0.35–0.85). The current results suggested that expression of ATM and cyclin B1 may be useful markers to identify patients with poor prognosis who may benefit from close follow-up and aggressive therapy in pancreatic neuroendocrine tumors.


Pancreatic neuroendorcine tumors ATM Cyclin B1 p53 Prognosis 


Conflicts of interest



  1. 1.
    Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wang DS, Zhang DS, Qiu MZ, Wang ZQ, Luo HY, Wang FH, et al. Prognostic factors and survival in patients with neuroendocrine tumors of the pancreas. Tumour Biol. 2011;32(4):697–705.CrossRefPubMedGoogle Scholar
  3. 3.
    Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14:7798–803.CrossRefPubMedGoogle Scholar
  6. 6.
    Chung DC. Cyclin d1 in human neuroendocrine: tumorigenesis. Ann N Y Acad Sci. 2004;1014:209–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Chung DC, Brown SB, Graeme-Cook F, Seto M, Warshaw AL, Jensen RT, et al. Overexpression of cyclin d1 occurs frequently in human pancreatic endocrine tumors. J Clin Endocrinol Metab. 2000;85:4373–8.PubMedGoogle Scholar
  8. 8.
    Park M, Chae HD, Yun J, Jung M, Kim YS, Kim SH, et al. Constitutive activation of cyclin b1-associated cdc2 kinase overrides p53-mediated g2-m arrest. Cancer Res. 2000;60:542–5.PubMedGoogle Scholar
  9. 9.
    Innocente SA, Abrahamson JL, Cogswell JP, Lee JM. P53 regulates a g2 checkpoint through cyclin b1. Proc Natl Acad Sci USA. 1999;96:2147–52.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Igarashi T, Jiang SX, Kameya T, Asamura H, Sato Y, Nagai K, et al. Divergent cyclin b1 expression and rb/p16/cyclin d1 pathway aberrations among pulmonary neuroendocrine tumors. Mod Pathol. 2004;17:1259–67.CrossRefPubMedGoogle Scholar
  11. 11.
    Teoh N, Pyakurel P, Dan YY, Swisshelm K, Hou J, Mitchell C, et al. Induction of p53 renders ATM-deficient mice refractory to hepatocarcinogenesis. Gastroenterology. 2010;138:1155–65. e1-2.CrossRefPubMedGoogle Scholar
  12. 12.
    Corbo V, Beghelli S, Bersani S, Antonello D, Talamini G, Brunelli M, et al. Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. Ann Oncol. 2012;23(1):127–34.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to pi-3 kinase. Science. 1995;268:1749–53.CrossRefPubMedGoogle Scholar
  14. 14.
    Bose S, Yap LF, Fung M, Starzcynski J, Saleh A, Morgan S, et al. The atm tumour suppressor gene is down-regulated in ebv-associated nasopharyngeal carcinoma. J Pathol. 2009;217:345–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Kang B, Guo RF, Tan XH, Zhao M, Tang ZB, Lu YY. Expression status of ataxia-telangiectasia-mutated gene correlated with prognosis in advanced gastric cancer. Mutat Res. 2008;638:17–25.CrossRefPubMedGoogle Scholar
  16. 16.
    Xing J, Wu X, Vaporciyan AA, Spitz MR, Gu J. Prognostic significance of ataxia-telangiectasia mutated, DNA-dependent protein kinase catalytic subunit, and ku heterodimeric regulatory complex 86-kd subunit expression in patients with nonsmall cell lung cancer. Cancer. 2008;112:2756–64.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ye C, Cai Q, Dai Q, Shu XO, Shin A, Gao YT, et al. Expression patterns of the atm gene in mammary tissues and their associations with breast cancer survival. Cancer. 2007;109:1729–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Grabsch H, Dattani M, Barker L, Maughan N, Maude K, Hansen O, et al. Expression of DNA double-strand break repair proteins atm and brca1 predicts survival in colorectal cancer. Clin Cancer Res. 2006;12:1494–500.CrossRefPubMedGoogle Scholar
  19. 19.
    Yu G, Zhu MH, Zhu Z, Ni CR, Zheng JM, Li FM. Expression of atm protein and its relationship with p53 in pancreatic carcinoma with tissue array. Pancreas. 2004;28:421–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Innocente SA, Lee JM. P53 is a nf-y- and p21-independent, sp1-dependent repressor of cyclin b1 transcription. FEBS Lett. 2005;579:1001–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Mashal RD, Lester S, Corless C, Richie JP, Chandra R, Propert KJ, et al. Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res. 1996;56:4159–63.PubMedGoogle Scholar
  22. 22.
    Kawamoto H, Koizumi H, Uchikoshi T. Expression of the g2-m checkpoint regulators cyclin b1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses. Am J Pathol. 1997;150:15–23.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Soria JC, Jang SJ, Khuri FR, Hassan K, Liu D, Hong WK, et al. Overexpression of cyclin b1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res. 2000;60:4000–4.PubMedGoogle Scholar
  24. 24.
    Hassan KA, Ang KK, El-Naggar AK, Story MD, Lee JI, Liu D, et al. Cyclin b1 overexpression and resistance to radiotherapy in head and neck squamous cell carcinoma. Cancer Res. 2002;62:6414–7.PubMedGoogle Scholar
  25. 25.
    Bjorck E, Ek S, Landgren O, Jerkeman M, Ehinger M, Bjorkholm M, et al. High expression of cyclin b1 predicts a favorable outcome in patients with follicular lymphoma. Blood. 2005;105:2908–15.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Jae Uk Shin
    • 1
  • Chang Hoon Lee
    • 1
  • Kyu Taek Lee
    • 1
    • 4
    Email author
  • Jong Kyun Lee
    • 1
  • Kwang Hyuck Lee
    • 1
  • Kwang Min Kim
    • 1
  • Kyoung-Mee Kim
    • 2
  • Sang-Mo Park
    • 3
  • Jong Chul Rhee
    • 1
  1. 1.Department of Internal Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Department of Pathology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  3. 3.Department of PathologySoonchunhyang University Bucheon HospitalBucheonSouth Korea
  4. 4.Division of Gastroenterology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea

Personalised recommendations