A Novel HOXA10-Associated 5-Gene–Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma

Author:

Kisling Sophia G.1ORCID,Atri Pranita1ORCID,Shah Ashu1ORCID,Cox Jesse L.2ORCID,Sharma Sunandini2ORCID,Smith Lynette M.3ORCID,Ghersi Dario4ORCID,Batra Surinder K.156ORCID

Affiliation:

1. 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

2. 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.

3. 3Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska.

4. 4School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska Omaha, Omaha, Nebraska.

5. 5Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

6. 6Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.

Abstract

Abstract Purpose: Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. Experimental Design: We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by IHC analysis of PDAC-resected STS and LTS tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses. Results: We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (P = 0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, homeobox gene HOXA10, and a 5-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in STSs and a strong association with poor survival. This signature was further associated with the proportion of T cells and macrophages found in STSs and LTSs, demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven prognostic signature is associated with immune suppression and enhanced tumorigenesis. Conclusions: Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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