The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients

Xing Huang; Yipeng Feng; Dawei Ma; Hanlin Ding; Gaochao Dong; Yan Chen; Xiaochen Huang; Jingyuan Zhang; Xinyu Xu; Chen Chen

doi:10.3389/fmolb.2022.887887

The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients

Front Mol Biosci. 2022 Aug 26:9:887887. doi: 10.3389/fmolb.2022.887887. eCollection 2022.

Authors

Xing Huang¹, Yipeng Feng^{2

3

4}, Dawei Ma¹, Hanlin Ding^{2

3

4}, Gaochao Dong^{2

3}, Yan Chen¹, Xiaochen Huang¹, Jingyuan Zhang¹, Xinyu Xu¹, Chen Chen⁵

Affiliations

¹ Department of Pathology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
² Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China.
³ Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.
⁴ The Fourth Clinical College of Nanjing Medical University, Nanjing, China.
⁵ Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precancerous lesion, with increasing incidence in recent years. However, the mechanisms of IPMN progression into invasive cancer remain unclear. The mRNA expression data of IPMN/PAAD patients were extracted from the TCGA and GEO databases. First, based on GSE19650, we analyzed the molecular alterations, tumor stemness, immune landscape, and transcriptional regulation of IPMN progression. The results indicated that gene expression changed dramatically, specifically at the intraductal papillary-mucinous adenoma (IPMA) stage. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Kyoto Encyclopedia of Genes and Genomes (GSEA) pathway analyses showed that glycoprotein-related, cell cycle, and P53 pathways displayed the most significant changes during progression. With IPMN progression, tumor stemness increased continuously, and KRAS, ERBB3, RUNX1, and ELF3 are essential driver genes affecting tumor stemness. Motif analysis suggested that KLF4 may be a specific transcription factor that regulates gene expression in the IPMA stage, while MYB and MYBL1 control gene expression in the IPMC and invasive stages, respectively. Then, GSE19650 and GSE71729 transcriptome data were combined to perform the least absolute shrinkage and selection operator (LASSO) method and Cox regression analysis to develop an 11-gene prediction model (KCNK1, FHL2, LAMC2, CDCA7, GPX3, C7, VIP, HBA1, BTG2, MT1E, and LYVE1) to predict the prognosis of pancreatic cancer patients. The reliability of the model was validated in the GSE71729 and TCGA databases. Finally, 11 additional IPMN patients treated in our hospital were included, and the immune microenvironment changes during IPMN progression were analyzed by immunohistochemistry (IHC). IHC results suggest that Myeloid-derived suppressor cells (MDSCs) and macrophages may be key in the formation of immunosuppressive microenvironment of IPMN progression. Our study deepens our understanding of IPMN progression, especially the changes in the immune microenvironment. The findings of this work may contribute to the development of new therapeutic strategies for IPMN.

Keywords: The Cancer Genome Atlas Program; gene expression omnibus; immunohistochemistry; intraductal papillary mucinous neoplasm; microenvironment.