Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancers in the United States. The five-year survival rate for patients with PDAC remains dismal. Identification of biomarkers for early diagnosis of PDAC and pre-cancer pancreatic intraepithelial neoplasia (PanIN) lesions with risk of progression to PDAC is critically needed. We hypothesized that differentially expressed genes and regulatory pathways in PanIN and PDAC compared to normal duct epithelium (ND) may represent biomarkers of development of malignancy. We used Affymetrix Human Transcriptome Arrays 2.0 to establish gene expressionprofiles in ND, low-grade PanIN, and PDAC epithelium. Total RNA was isolated after laser capture microdissection (LCM) of frozen tissue sections and then used for producing hybridization-ready DNA. Hybridization quality control was performed with Expression Console 1.4 software and background corrected/normalized data were analyzed with Transcriptome Analysis Console (TAC) 3.1 and the ASSIGN algorithm. We tested RNA from 22 LCM samples (9 PDACs, 5 PanINs, and 8 ND), including 4 matched trios of ND, PanIN and PDAC from the same patients. Differential expression analysis with one-way between subject ANOVA revealed over 2000 genes differentially expressed in PDAC and PanIN vs. ND group (filter criteria up/down >2; ANOVA p<0.05). The most frequent alteration in PanIN compared to ND samples was upregulation of 433 genes and in PDAC compared to ND downregulation of 566. We found 60 (40 coding) upregulated genes and 750 downregulated genes (filter criteria up/down >1.5; ANOVA p<0.05) in both PanIN and PDAC vs. ND epithelium. Signaling pathway analysis of WikiPathways showed a number of significantly altered pathways in PDAC and PanIN compared to ND including the Gastric Cancer Network 1 with upregulated S100P in both PanIN and PDAC whereas other genes including CENPF, KIF20B,TPX2, and UBE2C were upregulated in PDAC only. Using the ASSIGN algorithm and the Kruskal-Willis test for analysis of difference in pathway activity, we found additional regulatory pathways with altered activity including Nuclear Receptor meta-pathway with reduced overall score in PDAC compared to PanIN and ND samples. In summary, over 400 genes were significantly up-regulated in pre-cancer PanIN lesions compared to normal duct epithelium, whereas gene down-regulation was the most frequent alteration in PDAC. Sixty genes, including 40 coding genes were up-regulated in both PDAC and PanIN. The altered pathways associated with the differentially expressed genes may represent an approach for integrated biomarker testing of neoplastic progression. Citation Format: Elena V. Komissarova, Jorge Sepulveda, Sarawut Kongkarnka, Maryam Shirazi, Brynn Levy, Claudia Cujar, Antonia R. Sepulveda. Human transcriptome alterations in pre-cancer and cancer epithelium identify candidate biomarkers of progression to pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 714. doi:10.1158/1538-7445.AM2017-714
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