Combination Immunohistochemistry for SMAD4 and Runt-related Transcription Factor 3 May Identify a Favorable Prognostic Subgroup of Pancreatic Ductal Adenocarcinomas

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Nov 5

PMID 29100342

Authors

Yangkyu Lee

Hyejung Lee

Hyunjin Park

Jin-Won Kim

Jin-Hyeok Hwang

Jaihwan Kim

Yoo-Seok Yoon

Ho-Seong Han

Haeryoung Kim

Affiliations

Soon will be listed here.

Abstract

Purposes: SMAD4/DPC4 mutations have been associated with aggressive behavior in pancreatic ductal adenocarcinomas (PDAC), and it has recently been suggested that RUNX3 expression combined with SMAD4 status may predict the metastatic potential of PDACs. We evaluated the prognostic utility of SMAD4/RUNX3 status in human PDACs by immunohistochemistry.

Materials And Methods: Immunohistochemical stains were performed for SMAD4 and RUNX3 on 210 surgically resected PDACs, and the results were correlated with the clinicopathological features.

Results: Loss of SMAD4 expression was associated with poor overall survival (OS) ( = 0.015) and progression-free survival (PFS) ( = 0.044). Nuclear RUNX3 expression was associated with decreased OS ( = 0.010) and PFS ( = 0.009), and more frequent in poorly differentiated PDACs ( = 0.037). On combining RUNX3/SMAD4 status, RUNX3-/SMAD4+ PDACs demonstrated longer OS ( = 0.008, median time; RUNX3-/SMAD4+ 34 months, others 17 months) and PFS ( = 0.009, median time; RUNX3-/SMAD4+ 29 months, others 8 months) compared to RUNX3+/SMAD4+ and SMAD4- groups; RUNX3-/SMAD4+ was a significant independent predictive factor for both OS [ = 0.025, HR 1.842 (95% CI 1.079-3.143)] and PFS [ = 0.020, HR 1.850 (95% CI 1.100-3.113)].

Conclusions: SMAD4-positivity with RUNX3-negativity was a significant independent predictive factor for favorable OS and PFS in PDAC. This is the first and large clinicopathological study of RUNX3/SMAD4 expression status in human PDAC. Combination immunohistochemistry for SMAD4 and RUNX3 may help identify a favorable prognostic subgroup of PDAC.

References

Whittle M, Izeradjene K, Rani P, Feng L, Carlson M, DelGiorno K . RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. Cell. 2015; 161(6):1345-60. PMC: 4458240. DOI: 10.1016/j.cell.2015.04.048. View

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

Whittle M, Hingorani S . Runx3 and Cell Fate Decisions in Pancreas Cancer. Adv Exp Med Biol. 2017; 962:333-352. DOI: 10.1007/978-981-10-3233-2_21. View

Shugang X, Hongfa Y, Jianpeng L, Xu Z, Jingqi F, Xiangxiang L . Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis. Transl Oncol. 2016; 9(1):1-7. PMC: 4800056. DOI: 10.1016/j.tranon.2015.11.007. View

Nevadunsky N, Barbieri J, Kwong J, Merritt M, Welch W, Berkowitz R . RUNX3 protein is overexpressed in human epithelial ovarian cancer. Gynecol Oncol. 2008; 112(2):325-30. DOI: 10.1016/j.ygyno.2008.09.006. View

Collisson E, Sadanandam A, Olson P, Gibb W, Truitt M, Gu S . Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011; 17(4):500-3. PMC: 3755490. DOI: 10.1038/nm.2344. View

Iacobuzio-Donahue C, Fu B, Yachida S, Luo M, Abe H, Henderson C . DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009; 27(11):1806-13. PMC: 2668706. DOI: 10.1200/JCO.2008.17.7188. View

Seymour A, Hruban R, Redston M, Caldas C, Powell S, Kinzler K . Allelotype of pancreatic adenocarcinoma. Cancer Res. 1994; 54(10):2761-4. View

Chen F, Wang M, Bai J, Liu Q, Xi Y, Li W . Role of RUNX3 in suppressing metastasis and angiogenesis of human prostate cancer. PLoS One. 2014; 9(1):e86917. PMC: 3901713. DOI: 10.1371/journal.pone.0086917. View

10.

Lee K, Lee Y, Lee J, Ito K, Cinghu S, Kim J . Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer. Oncogene. 2010; 29(23):3349-61. DOI: 10.1038/onc.2010.79. View

11.

Huang B, Qu Z, Ong C, Tsang Y, Xiao G, Shapiro D . RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α. Oncogene. 2011; 31(4):527-34. PMC: 3697905. DOI: 10.1038/onc.2011.252. View

12.

Wilentz R, Iacobuzio-Donahue C, Argani P, McCarthy D, Parsons J, Yeo C . Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000; 60(7):2002-6. View

13.

Tascilar M, Skinner H, Rosty C, Sohn T, Wilentz R, Offerhaus G . The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001; 7(12):4115-21. View

14.

Biankin A, Morey A, Lee C, Kench J, Biankin S, Hook H . DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol. 2002; 20(23):4531-42. DOI: 10.1200/JCO.2002.12.063. View

15.

Crane C, Varadhachary G, Yordy J, Staerkel G, Javle M, Safran H . Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol. 2011; 29(22):3037-43. PMC: 3157965. DOI: 10.1200/JCO.2010.33.8038. View

16.

Demagny H, De Robertis E . Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling. Mol Cell Oncol. 2016; 3(1):e1025181. PMC: 4845174. DOI: 10.1080/23723556.2015.1025181. View

17.

Jones S, Zhang X, Parsons D, Cheng-Ho Lin J, Leary R, Angenendt P . Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321(5897):1801-6. PMC: 2848990. DOI: 10.1126/science.1164368. View

18.

Moffitt R, Marayati R, Flate E, Volmar K, Loeza S, Hoadley K . Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015; 47(10):1168-78. PMC: 4912058. DOI: 10.1038/ng.3398. View

19.

Lee C, Chuang L, Kimura S, Lai S, Ong C, Yan B . RUNX3 functions as an oncogene in ovarian cancer. Gynecol Oncol. 2011; 122(2):410-7. DOI: 10.1016/j.ygyno.2011.04.044. View

20.

Whittle M, Hingorani S . Disconnect between EMT and metastasis in pancreas cancer. Oncotarget. 2015; 6(31):30445-6. PMC: 4741540. DOI: 10.18632/oncotarget.5720. View