title: Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.affiliation: Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gauri R
authors.initials: GR
authors.lastname: Varadhachary
authors.affiliation: Department of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
mesh_terms: D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D001124:Argininosuccinate Synthase