SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases

Takashi Mizuno, Jordan M. Cloyd, Diego Vicente, Kiyohiko Omichi, Yun Shin Chun, Scott E. Kopetz, Dipen Maru, Claudius Conrad, Ching Wei D. Tzeng, Steven H. Wei, Thomas A. Aloia, Jean Nicolas Vauthey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Introduction: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). Methods: Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. Results: Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). Conclusion: SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.

Original languageEnglish
Pages (from-to)684-692
Number of pages9
JournalEuropean Journal of Surgical Oncology
Issue number5
StatePublished - May 2018
Externally publishedYes


  • Colorectal cancer
  • Colorectal liver metastases
  • Dorsophilia protein
  • Hepatectomy
  • KRAS
  • Mothers against decapentaplegic homolog 4


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