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. 2017 Sep 11;8(44):76699-76711.
doi: 10.18632/oncotarget.20815. eCollection 2017 Sep 29.

Combination immunohistochemistry for SMAD4 and Runt-related transcription factor 3 may identify a favorable prognostic subgroup of pancreatic ductal adenocarcinomas

Yangkyu Lee  1 , Hyejung Lee  2 , Hyunjin Park  2 , Jin-Won Kim  3 , Jin-Hyeok Hwang  3 , Jaihwan Kim  3 , Yoo-Seok Yoon  4 , Ho-Seong Han  4 , Haeryoung Kim  2
Affiliations

Combination immunohistochemistry for SMAD4 and Runt-related transcription factor 3 may identify a favorable prognostic subgroup of pancreatic ductal adenocarcinomas

Yangkyu Lee et al. Oncotarget. .

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) (p = 0.015) and progression-free survival (PFS) (p = 0.044). Nuclear RUNX3 expression was associated with decreased OS (p = 0.010) and PFS (p = 0.009), and more frequent in poorly differentiated PDACs (p = 0.037). On combining RUNX3/SMAD4 status, RUNX3-/SMAD4+ PDACs demonstrated longer OS (p = 0.008, median time; RUNX3-/SMAD4+ 34 months, others 17 months) and PFS (p = 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 [p = 0.025, HR 1.842 (95% CI 1.079-3.143)] and PFS [p = 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.

Keywords: RUNX3; SMAD4; immunohistochemistry; pancreatic ductal adenocarcinoma; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. Immunohistochemical stain results for RUNX3 and SMAD4 in PDACs and normal pancreatic parenchyma
(A) RUNX3 is not expressed in normal pancreatic tissue. A few scattered lymphocytes show nuclear RUNX3 expression. Representative PDACs with (B) no nuclear RUNX3 expression and (C) RUNX3 expression. (D) Intact SMAD4 expression in normal pancreatic tissue. PDACs with (E) SMAD4 loss, and (F) intact SMAD4 expression (original magnification x400).
Figure 2
Figure 2. Survival analysis results
Decreased overall survival (OS) (A) and progression-free survival (PFS) (B) are seen in PDACs with SMAD4 loss compared to those with intact SMAD4. RUNX3-expressing PDACs demonstrate decreased OS (C) and PFS (D) compared to RUNX3-negative tumors. RUNX3−/SMAD4+ PDACs show increased OS (E, G) and PFS (F, H) compared to the other PDACs. (G, H) “Other groups”: RUNX3−/SMAD4−, RUNX3+/SMAD4−, RUNX3+/SMAD4+ PDACs).
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