Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: a systematic review and meta-analysis

Background: Approximately 5.0%-24.2% of colorectal cancers (CRCs) have activating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of mutation of SMAD4 gene in CRC. Methods: A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between mutations of SMAD4 gene and the demographic and clinicopathological characteristics in patients with CRC. The hazard ratios with 95% confidence intervals were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). Results: Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from five studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% confidence interval [95% CI] 1.28–1.67, P=0.001), the summary HR for PFS/RFS was 1.59 (95% CI=1.14–2.22, P=0.006). In terms of clinicopathology parameters, SMAD4 mutations were associated with tumor location (odds ratio [OR]= 1.15, colon/rectum, 95% CI=1.01-1.31, P=0.042), TNM stage (OR=0.78, stage Ⅰ-Ⅲ/Ⅳ, [95% CI] 0.63-0.97, P=0.025), lymph node metastases (OR=1.42, N+/N0, 95% CI=1.20-1.67, P<0.001), mucinous differentiation (OR=2.23, 95% CI=1.85-2.70, P<0.001) and rat sarcoma viral oncogene homolog (RAS) status (OR=0.47, RAS wild-type/ RAS mutation, 95% CI=0.30-0.73, P=0.001). No connection was found with age, gender, tumor grade, microsatellite instability (MSI) status and b-viral oncogene homolog B1(BRAF) status. Besides, publication bias was not observed in all studies. Conclusions: This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastases and tumor mucinous differentiation. It was indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies were needed to further confirm this conclusion. As SMAD4 mutation was found to be closely associated with RAS mutations, their relationship was worth further investigating.