SMAD4 loss predicts worse overall and distant metastasis‐free survival in patients with resected pancreatic adenocarcinoma

Background In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA–seq...

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Bibliographic Details
Published in:Cancer 2024-02, Vol.130 (3), p.476-484
Main Authors: Anstadt, Emily J., Carmona, Ruben, Berlin, Eva, Yegya‐Raman, Nikhil, Venigalla, Sriram, Reddy, Vishruth, Williams, Graeme R., Leibensperger, Mark R., Wojcieszynski, Andrzej, Baumann, Brian C., Lee, Major K., Plastaras, John P., Furth, Emma E., Mell, Loren K., Metz, James M., Ben‐Josef, Edgar
Format: Article
Language:English
Subjects:
Aberration
Adenocarcinoma
Adenocarcinoma - genetics
Adenocarcinoma - surgery
biomarker
Biomarkers
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cancer
Gene expression
Gene sequencing
Genomes
genomic aberration
Genomics
Hazard identification
Health hazards
Humans
Metastases
Metastasis
mothers against decapentaplegic homolog 4 (SMAD4)
Pancreas
Pancreatic cancer
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - surgery
Performance prediction
Prognosis
Proportional Hazards Models
RNA sequencing
Smad4 protein
Smad4 Protein - genetics
Statistical models
Survival
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Summary:Background In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA–sequencing (RNA‐seq) expression is a robust method for predicting overall survival (OS) and distant metastasis‐free survival (DMFS) in patients with resected pancreatic adenocarcinoma. Methods Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I–III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA‐seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA‐seq via multivariable models and receiver operator characteristic curves. Results In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00–2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87–2.03; p = .19). Low SMAD4 RNA‐seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17–2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14–2.54; p = .009). In the ICGC, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86–.94) and DMFS (AUC, .84; 95% CI, .82–.87). Conclusions In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA‐seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA‐seq expression may be a useful marker to predict metastatic spread. Via The Cancer Genome Atlas and the International Cancer Genome Consortium, 322 patients with resected stage I–III pancreatic adenocarcinoma were studied. Compared to SMAD4 (mothers against decapentaplegic homolog 4) genomic aberrations, increased SMAD4 messenger RNA–sequencing (RNA‐seq) expression was found to be associated with both improved overall survival and distant metastasis‐free survival, which suggests that SMAD4 RNA‐seq expression may be a better marker for predicting metastatic spread, and therefore may have utility in clinical risk stratification for treatment planning.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.35058