Multivariate Analysis of Immunohistochemical Evaluation of Protein Expression in Pancreatic Ductal Adenocarcinoma Reveals Prognostic Significance for Persistent Smad4 Expression Only

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2012 Feb 22

PMID 22351431

Citations 19

Authors

Niki A Ottenhof

Folkert H M Morsink

Fiebo Ten Kate

Cornelis J F van Noorden

G Johan A Offerhaus

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6 months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear.

Methods And Results: To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p = 0.004), tumor free resection margins (p = 0.044) and Smad4 expression (p = 0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival.

Conclusions: Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies.

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References

Maple J, Smyrk T, Boardman L, Johnson R, Thibodeau S, Chari S . Defective DNA mismatch repair in long-term (> or =3 years) survivors with pancreatic cancer. Pancreatology. 2005; 5(2-3):220-7. DOI: 10.1159/000085275. View

Butturini G, Stocken D, Wente M, Jeekel H, Klinkenbijl J, Bakkevold K . Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch Surg. 2008; 143(1):75-83. DOI: 10.1001/archsurg.2007.17. View

Bergmann F, Aulmann S, Wente M, Penzel R, Esposito I, Kleeff J . Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40. J Clin Pathol. 2006; 59(6):580-4. PMC: 1860388. DOI: 10.1136/jcp.2005.027292. View

Rasheed Z, Yang J, Wang Q, Kowalski J, Freed I, Murter C . Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010; 102(5):340-51. PMC: 2831049. DOI: 10.1093/jnci/djp535. View

Showalter T, Winter K, Berger A, Regine W, Abrams R, Safran H . The influence of total nodes examined, number of positive nodes, and lymph node ratio on survival after surgical resection and adjuvant chemoradiation for pancreatic cancer: a secondary analysis of RTOG 9704. Int J Radiat Oncol Biol Phys. 2010; 81(5):1328-35. PMC: 3038247. DOI: 10.1016/j.ijrobp.2010.07.1993. View

Hsu C, Herman J, Corsini M, Winter J, Callister M, Haddock M . Adjuvant chemoradiation for pancreatic adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Ann Surg Oncol. 2010; 17(4):981-90. PMC: 2840672. DOI: 10.1245/s10434-009-0743-7. View

Song X, Wang H, Logsdon C, Rashid A, Fleming J, Abbruzzese J . Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer. 2010; 117(4):734-43. PMC: 4403266. DOI: 10.1002/cncr.25483. View

Hahn S, Schutte M, Hoque A, Moskaluk C, DA COSTA L, Rozenblum E . DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996; 271(5247):350-3. DOI: 10.1126/science.271.5247.350. View

Nakata B, Wang Y, Yashiro M, Nishioka N, Tanaka H, Ohira M . Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002; 8(8):2536-40. View

10.

Milne A, Sitarz R, Carvalho R, Carneiro F, Offerhaus G . Early onset gastric cancer: on the road to unraveling gastric carcinogenesis. Curr Mol Med. 2007; 7(1):15-28. DOI: 10.2174/156652407779940503. View

11.

Koorstra J, Karikari C, Feldmann G, Bisht S, Rojas P, Offerhaus G . The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009; 8(7):618-26. PMC: 2678175. DOI: 10.4161/cbt.8.7.7923. View

12.

Bhatti I, Peacock O, Awan A, Semeraro D, Larvin M, Hall R . Lymph node ratio versus number of affected lymph nodes as predictors of survival for resected pancreatic adenocarcinoma. World J Surg. 2010; 34(4):768-75. DOI: 10.1007/s00268-009-0336-4. View

13.

David M, Lepage C, Jouve J, Jooste V, Chauvenet M, Faivre J . Management and prognosis of pancreatic cancer over a 30-year period. Br J Cancer. 2009; 101(2):215-8. PMC: 2720200. DOI: 10.1038/sj.bjc.6605150. View

14.

Blackford A, Serrano O, Wolfgang C, Parmigiani G, Jones S, Zhang X . SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009; 15(14):4674-9. PMC: 2819274. DOI: 10.1158/1078-0432.CCR-09-0227. View

15.

Wilentz R, Su G, Dai J, Sparks A, Argani P, Sohn T . Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas : a new marker of DPC4 inactivation. Am J Pathol. 2000; 156(1):37-43. PMC: 1868651. DOI: 10.1016/S0002-9440(10)64703-7. View

16.

Maitra A, Kern S, Hruban R . Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006; 20(2):211-26. DOI: 10.1016/j.bpg.2005.10.002. View

17.

Ghimenti C, Tannergard P, Wahlberg S, Liu T, Giulianotti P, Mosca F . Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer. 1999; 80(1-2):11-6. PMC: 2363009. DOI: 10.1038/sj.bjc.6690314. View

18.

Maitra A, Adsay N, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron J . Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol. 2003; 16(9):902-12. DOI: 10.1097/01.MP.0000086072.56290.FB. View

19.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M . Cancer statistics, 2009. CA Cancer J Clin. 2009; 59(4):225-49. DOI: 10.3322/caac.20006. View

20.

Kunkel T, Erie D . DNA mismatch repair. Annu Rev Biochem. 2005; 74:681-710. DOI: 10.1146/annurev.biochem.74.082803.133243. View