Clinicopathological significance of SMAD4 loss in pancreatic ductal adenocarcinomas: a systematic review and meta-analysis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality. Although advances have been made in understanding the pathogenesis of PDAC, the outcome still remains poor. The aim of this study is to conduct a meta-analysis to evaluate the precise association between SMAD4 loss and clinicopathological significance in PDAC. A literature search was made in PubMed, Web of Science, Google scholar, and EMBASE for related publications. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed, Odds Ratio or Hazard Ratio with corresponding confidence intervals was calculated and summarized. 12 relevant articles were included for full review in detail and meta-analysis. The frequency of SMAD4 protein loss was significantly increased in PDAC than in nonmalignant pancreatic tissue, Odd Ratio was 0.05 with 95% confidence interval 0.01-0.23, p<0.0001. SMAD4 loss was significantly associated with poor overall survival in patients with PDAC, Hazard Ratio was 0.61 with 95% confidence interval 0.38-0.99, p=0.05. SMAD4 loss was not correlated with the size, grades, and lymph node metastasis of PDAC. In conclusion, SMAD4 is a biomarker for the diagnosis of PDAC. SMAD4 loss is significantly related to poor prognosis in patients with PDAC.

Deletion of Smad4 reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression

“…For example, the meta‐analysis conducted by Wang et al . suggested that SMAD4 could be indicative for diagnosing pancreatic duct adenocarcinoma, and SMAD4 loss showed a significant correlation with a poor survival of patients with pancreatic duct adenocarcinomas . Baraniskin et al .…”

“…For example, the meta-analysis conducted by Wang et al suggested that SMAD4 could be indicative for diagnosing pancreatic duct adenocarcinoma, and SMAD4 loss showed a significant correlation with a poor survival of patients with pancreatic duct adenocarcinomas. 29 Baraniskin et al identified a reduction of SMAD4 expression in patients with metastatic colorectal cancer who had received combination chemotherapy, which was related with a shorter overall survival rate. 30 Interestingly, immunohistochemistry in our study demonstrated that the protein expression of SMAD4 in patients with NASH was significantly increased compared with normal controls, possibly because chronic inflammation shifts hepatocytic Smad phospho-isoform signaling from tumor suppression to carcinogenesis, accelerating liver fibrosis.…”

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

“…SMAD4 (or DPC4 ) is a well-known tumor suppressor gene that is inactivated in the late stages of pancreatic carcinogenesis: SMAD4 inactivation has been reported in ~50% of PDACs and in ~30% of high-grade pancreatic intraepithelial neoplasia (PanIN-3) [ 9 – 12 ]. Although the majority of clinicopathological studies, including our present study, have demonstrated associations between SMAD4 loss in PDACs and poor prognoses, there are also reports showing no significant correlations with survival, or even evidence for improved survival in PDACs with SMAD4 loss [ 13 – 17 ]. Loss of SMAD4 protein expression has been demonstrated to be a sensitive and specific surrogate marker for SMAD4 alteration, independent of whether SMAD4 inactivation occurred by homozygous deletions or by loss of heterozygosity, and the presence of intact SMAD4 protein expression corresponds to tumors with at least one wild-type allele (i.e.…”

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

“…Recent studies have confirmed that inactivation of SMAD4 is the strongest predictor of metastatic recurrence [ 10 ]. Furthermore, review and meta-analysis of the literature data confirmed the negative clinicopathological significance of SMAD4 loss in PDACs [ 11 ]. Although SMAD4 gene deletion is associated with a poor prognosis, however, it exposes PDAC cells to a metabolic vulnerability.…”