A Novel BCAA-catabolism Related Gene Signature for Overall Survival Prediction of Pancreatic Carcinoma

抄録

Abstract
Background Branched-chain amino acid (BCAA) metabolism plays an important role in the pancreatic carcinogenesis, but its mechanism remains unclear. Hence, this study was performed to investigate comprehensively the value of genes related to BCAA catabolism in pancreatic cancer. Methods The online GEO, TCGA, and ICGC datasets were searched for bioinformatic analysis. Univariate Cox and Lasso regression were applied to construct a predictive model. Human cancer cell lines and tissue microarray (TMA) were applied for validation. Results From the 48 BCAA-catabolism enzyme (BCE) genes, a 5-gene risk-score (ABAT, ACAT1, BCAT1, BCAT2, and DBT) was constructed. Patients in high-risk and low-risk groups stratified by risk-score, indicated significantly different OS (for TCGA, 1.62 years vs. 1.90 years, p = 0.02; for ICGC, 1.25 years vs. 1.87 years, p = 0.01; for GEO, 1.49 years vs. 2.63 years, p = 0.01). Given the clinical parameters, the risk-score was independent predictor for prognosis [for TCGA, hazard ratio (HR) = 3.16, 95% confidence interval (CI) = 1.63–6.12, p < 0.01; for ICGC, HR = 3.16, 95% CI = 1.04–2.35, p = 0.03]. Among the five genes, ABAT and BCAT2 were hub genes with favorable prognosis value, which validated by TMA immunohistochemistry (IHC) staining. Immune infiltration analysis indicated high-risk group enriched macrophage, and decreased positive cell density of stromal CD68⁺ macrophage in TMA was observed for BCAT2 with low-expression than high-expression cases (p < 0.05). Conclusion A risk-score involving five BCE genes was proposed to predict the poor prognosis of pancreatic cancer. Based on the immune infiltration analysis, the underlying mechanism might be BCAT2 associated stromal macrophage infiltration.