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J Cancer. 2019 Jul 10;10(17):4123-4131. doi: 10.7150/jca.30883. eCollection 2019.

The Loss of SMAD4/DPC4 Expression Associated with a Strongly Activated Hedgehog Signaling Pathway Predicts Poor Prognosis in Resected Pancreatic Cancer.

Xu JZ1,2,3,4, Wang WQ1,2,3,4, Zhang WH1,2,3,4, Xu HX1,2,3,4, Gao HL1,2,3,4, Zhang SR1,2,3,4, Wu CT1,2,3,4, Li S1,2,3,4, Li H1,2,3,4, Xu J1,2,3,4, Yu XJ1,2,3,4, Liu L1,2,3,4.

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Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Shanghai Pancreatic Cancer Institute, Shanghai, China.
Pancreatic Cancer Institute, Fudan University, Shanghai, China.


Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway. However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear. Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance. Results: SMAD4 lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC. The mutational status of p16 had no effect on patient survival. High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses. Pearson's χ2 test showed a medium correlation between the SMAD4 lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001). Patients with the SMAD4 lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study. Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.


Hedgehog signaling pathway; SMAD4/DPC4; driver genes; pancreatic ductal adenocarcinoma; prognosis

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