Association between <i>SMAD4</i> Mutations and <i>GATA6</i> Expression in Paired Pancreatic Ductal Adenocarcinoma Tumor Specimens: Data from Two Independent Molecularly-Characterized Cohorts

Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). <i>SMAD4</i> alterations and low <i>GATA6</i> expression/modified “Moffitt” basal-like phenotype have each been associated with infe...

Full description

Bibliographic Details
Main Authors: Joshua D. Greendyk, William E. Allen, H. Richard Alexander, Toni Beninato, Mariam F. Eskander, Miral S. Grandhi, Timothy J. Kennedy, Russell C. Langan, Jason C. Maggi, Subhajyoti De, Colin M. Court, Brett L. Ecker
Format: Article
Language:English
Published: MDPI AG 2023-11-01
Series:Biomedicines
Subjects:
Online Access:https://www.mdpi.com/2227-9059/11/11/3058
Description
Summary:Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). <i>SMAD4</i> alterations and low <i>GATA6</i> expression/modified “Moffitt” basal-like phenotype have each been associated with inferior survival uniquely for patients receiving 5-FU-based therapies. <i>SMAD4</i> may directly regulate the expression of <i>GATA6</i> in PDAC, pointing to a common predictive biomarker. To evaluate the relationship between <i>SMAD4</i> mutations and <i>GATA6</i> expression in human PDAC tumors, patients with paired <i>SMAD4</i> mutation and <i>GATA6</i> mRNA expression data in the TCGA and CPTAC were identified. In 321 patients (TCGA: n = 180; CPTAC: n = 141), the rate of <i>SMAD4</i> alterations was 26.8%. The rate of <i>SMAD4</i> alteration did not vary per tertile of normalized <i>GATA6</i> expression (TCGA: <i>p</i> = 0.928; CPTAC: <i>p</i> = 0.828). In the TCGA, <i>SMAD4</i> alterations and the basal-like phenotype were each associated with worse survival (log rank <i>p</i> = 0.077 and <i>p</i> = 0.080, respectively), but their combined presence did not identify a subset with uniquely inferior survival (<i>p</i> = 0.943). In the CPTAC, the basal-like phenotype was associated with significantly worse survival (<i>p</i> < 0.001), but the prognostic value was not influenced by the combined presence of <i>SMAD4</i> alterations (<i>p</i> = 0.960). <i>SMAD4</i> alterations were not associated with poor clinico-pathological features such as poor tumor grade, advanced tumor stage, positive lymphovascular invasion (LVI), or positive perineural invasion (PNI), compared with <i>SMAD4</i>-wildtype. Given that <i>SMAD4</i> mutations were not associated with <i>GATA6</i> expression or Moffitt subtype in two independent molecularly characterized PDAC cohorts, distinct biomarker-defined clinical trials are necessary.
ISSN:2227-9059