Argininosuccinate synthetase 1 (ASS1), the rate-limiting
enzyme for
arginine biosynthesis, is expressed in many types of human
malignancies. Recent studies showed that ASS1 may have
tumor suppressor function and that ASS1 deficiency is associated with clinical aggressiveness in
nasopharyngeal carcinoma, myxofibrosarcomas and
bladder cancer. The goal of this study was to evaluate the prognostic impact of ASS1 expression in patients with pancreatic ductal
adenocarcinoma (PDAC). Our study included two independent cohorts: untreated cohort, which was comprised of 135 patients with PDAC who underwent
pancreatoduodenectomy (PD) without pre-operative
neoadjuvant therapy, and treated cohort, which was comprised of 122 patients with PDAC who have completed
neoadjuvant therapy and PD. The expression level of ASS1 was evaluated by immunohistochemistry and the results were correlated with clinicopathologic parameters and survival using SPSS statistics. Our study showed that 12% of PDAC in untreated cohort and 15% of PDAC in treated cohort has low expression of ASS1 (ASS1-low). ASS1-low was associated with higher recurrence (p = 0.045), shorter disease-free survival (DFS, 4.8 ± 1.6 months vs 15.3 ± 2.2 months, p = 0.001) and shorter overall survival (OS, 14.6 ± 6.4 months vs 26.5 ± 3.5 months, p = 0.005) in untreated cohort and shorter OS in treated cohort compared to ASS1-high
tumors. In multivariate analysis, ASS1-low (HR: 0.45, 95% CI: 0.26-0.79, p = 0.005) was an independent prognostic factor for DFS in untreated cohort and an independent prognostic factor for OS (HR: 0.56, 95% CI: 0.32-0.97, p = 0.04) in treated cohort. Our results provide supporting evidence for future clinical trial using
arginine deprivation agents either alone or in combination with conventional
chemotherapy in treating
pancreatic cancer.