Abstract 96: Targeted sequencing from endoscopic ultrasound-guided fine needle aspirates of pancreatic ductal adenocarcinoma
Authors: Joo Kyung Park, Kwang Hyuk Lee, Jong Kyun Lee, Kyu Taek Lee, Woong-Yang Park, Dae-Soon Son
Journal: Cancer Research (2016)

Abstract Next-generation sequencing (NGS) that enables the analyses of massively parallel sequences of DNA can advance the understanding of the underlying molecular pathophysiologies of cancer. Such recent genomic analyses have revealed a complex mutational landscape in surgical specimens of PDAC. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is used in the diagnosis of pancreatic cancer. Several genomic analyses using EUS-FNA in PDAC have been undertaken in a small number of patients. This study evaluated the feasibility of targeted NGS of specimens obtained using EUS-FNA to clarify genetic markers associated with the prognosis of pancreatic cancer. One hundred sixty six patients who underwent EUS-FNA with pathologically confirmed PDAC were included. Genomic DNA was extracted and quality control metrics of DNA analytes were measured. The specimens that passed a quality control test (N = 101, 61%) underwent NGS using a customized cancer panel (CancerSCAN) enriched in the exons of 83 genes. Clinical prognostic factors associated with survival in PDAC were age, performance status, CA 19-9 level, curative resection, chemotherapy, tumor mass size, tumor location, stage and metastasis site in univariate analysis (P = 0.020, &amp;lt;0.001, 0.015, 0.022, &amp;lt;0.001, &amp;lt;0.001, 0.031, 0.024 and 0.028, respectively). Multivariate Cox proportional-hazards analysis revealed chemotherapy (P &amp;lt; 0.001, hazard ratio (HR) = 5.7, 95% CI, 2.8 to 11.3) and tumor mass size (P = 0.001, HR = 0.4, 95% CI, 0.2 to 0.7) as independent prognostic factors. Each patient had different numbers of genetic alterations ranging from 0 to 17, and 99% of the patients had at least a single genetic alteration. KRAS mutation was found in 86 patients (86%); KRAS variant allele frequency ranged from 2 to 79%. The frequencies of major gene mutations responsible for PDACs were KRAS 86%, CDKN2A 22%, TP53 72%, SMAD4 25% and BRCA 14%. Genetic alterations associated with survival were ARID1A, AURKB1, CDK4, ERBB4, HNF1A, JAK3, MPL, PIK3R, PTCH1, STK11 and TOP1 in univariate analysis. In multivariate analysis, CDK4, HNF1A, MPL, PIK3R, PTCH1, STK11 and TOP1 mutations were independently associated with overall survival (P = 0.011, P = 0.001, P = 0.001, P = 0.005, P = 0.041, P = 0.050 and P = 0.003, respectively). KRAS gene (variant allele frequency 50%) and the EphB4 mutation were significantly associated with PDAC metastasis. ATRX and TERT genes were significantly associated with the pattern of metastasis in PDACs. ABL1 and BRAF mutations were significantly associated with stable disease as well as partial response to chemotherapy (P = 0.047 and P = 0.015, respectively). Targeted sequencing using EUS-FNA specimens in PDAC is feasible and shows similar genomic profiles in surgical specimens. Novel genes associated with survival, metastasis and chemotherapy response in PDAC were identified. Citation Format: Joo Kyung Park, Kwang Hyuk Lee, Jong Kyun Lee, Kyu Taek Lee, Woong-Yang Park, Dae-Soon Son. Targeted sequencing from endoscopic ultrasound-guided fine needle aspirates of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 96.