ArticleThe American journal of surgical pathology2015
Smad4 loss in esophageal adenocarcinoma is associated with an increased propensity for disease recurrence and poor survival.
Article in The American journal of surgical pathology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 2 syntheses or guidelines pooled it, 38 citations in OpenAlex.
- Perineural Invasion Is a Significant Indicator of High Malignant Degree and Poor Prognosis in Esophageal Cancer: A Systematic Review and Meta-Analysis.Frontiers in oncology · 2022Pooled it
- A systematic review and meta-analysis of prognostic biomarkers in resectable esophageal adenocarcinomas.Scientific reports · 2018Pooled it
- SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma.Clinical and translational science · 2021Trial
- Suppression of TRIM33 and SMAD4 Indicates a Possible Tumor-Suppressive Role in Esophageal Squamous Cell Carcinoma.Digestive diseases and sciences · 2026Article
- Patterns, Timing, and Survival of Recurrence After Surgery for Esophageal and Junctional Adenocarcinoma in the European Multicentre ENSURE Study.Annals of surgical oncology · 2026Article
- The Evolving Paradigm of Esophageal and Esophagogastric Junction Adenocarcinoma: Current Insights, Emerging Therapies, and Future Directions.Journal of cancer science and clinical therapeutics · 2025Article
- The impact of perineural invasion on prognosis in esophageal cancer patients after surgery: a systematic review and meta-analysis.Frontiers in oncology · 2025Review
- Diagnostic Value of Biomarkers in the Diagnosis of Cholangiocarcinoma and Its Benign Mimickers.Iranian journal of pathology · 2025Article
- Exploring Potential Biomarkers in Oesophageal Cancer: A Comprehensive Analysis.International journal of molecular sciences · 2024Review
- Review
- Landscape of Genetic Mutations in Appendiceal Cancers.Cancers · 2023Review
- Article
- Selective targeting BMP2 and 4 in SMAD4 negative esophageal adenocarcinoma inhibits tumor growth and aggressiveness in preclinical models.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Prognostic Roles of ZNF703 and SMAD4 Expression in Patients with Papillary Thyroid Cancer and Association with Nodal Metastasis.Indian journal of surgical oncology · 2022Article
- Next-Generation Sequencing of 487 Esophageal Adenocarcinomas Reveals Independently Prognostic Genomic Driver Alterations and Pathways.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- SMAD4 mutation correlates with poor prognosis in non-small cell lung cancer.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis.Molecular therapy. Nucleic acids · 2021Article
- Comprehensive Analysis of the Expression of TGF-Computational and mathematical methods in medicine · 2021Article
- Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus.Cellular and molecular gastroenterology and hepatology · 2021Article
- Drivers of Esophageal Adenocarcinoma and Opportunities for Cancer Interception.Cellular and molecular gastroenterology and hepatology · 2021Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Previously regarded as a rare neoplasm, the incidence of esophageal adenocarcinoma has risen rapidly in recent decades. It is often discovered late in the disease process and has a dismal prognosis. Current prognostic markers including clinical, radiographic, and histopathologic findings have limited utility and do not consider the biology of this deadly disease. Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors. Although Smad4 has been extensively studied in other gastrointestinal malignancies, its role in esophageal adenocarcinoma remains to be defined. Herein, we show, in a large cohort of esophageal adenocarcinomas, Smad4 loss by immunohistochemistry in 21 of 205 (10%) tumors and that Smad4 loss correlated with increased postoperative recurrence (P=0.040). Further, patients whose tumors lacked Smad4 had shorter time to recurrence (TTR) (P=0.007) and poor overall survival (OS) (P=0.011). The median TTR and OS of patients with Smad4-negative tumors was 13 and 16 months, respectively, as compared with 23 and 22 months, respectively, among patients with Smad4-positive tumors. In multivariate analyses, Smad4 loss was a prognostic factor for both TTR and OS, independent of histologic grade, lymphovascular invasion, perineural invasion, tumor stage, and lymph node status. Considering Smad4 loss correlated with postoperative locoregional and/or distant metastases, Smad4 was also assessed in a separate cohort of 5 locoregional recurrences and 43 metastatic esophageal adenocarcinomas. In contrast to primary tumors, a higher prevalence of Smad4 loss was observed in metastatic disease (44% vs. 10%). In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.