Integrated clinico-genomic characterization of pancreatic ductal adenocarcinoma in an Asian population.

Abstract

e16291 Background: Pancreatic cancer is a devastating malignancy with an extremely poor prognosis. However, the clinico-genomic understanding of pancreatic cancer that could play an important role to improve prognosis is highly limited, especially in Asian population. Methods: Using blood sample and primary pancreas tissues by endoscopic ultrasound guided fine needle biopsy (EUS-FNB) from 237 patients diagnosed with pancreatic ductal adenocarcinoma (PDA) at Seoul National University Bundang Hospital, WES and WTS were performed. Integrated clinico-genomic analysis was conducted by combining genomic data with diverse clinical information. Results: WES and WTS data were obtained from 205 and 93 patients, respectively. In WES, recurrent somatic mutations were identified in KRAS (89.3%), TP53 (68.8%), SMAD4 (22.4%) and CDKN2A (20.5%), and the overall mutation profile was not significantly different from TCGA dataset. Germline mutations related with hereditary cancer syndrome were found in 19 (9.3%), and BRCA2 mutation was the most common as in the Western data. At least one actionable mutation was reported in 61 (29.8%), and KRAS p.G12C, the emerging actionable mutation, was found in five (2.4%). In mutational signature analysis with single-base substitution (SBS), SBS1, SBS3 and SBS13 were identified in this cohort, and SBS3, a potential biomarker for DDR pathway related therapy, was positive in 25 (12.2%). Since this cohort contained 112 stage I-III (47.3%) and 125 stage IV (52.7%), genetic features according to stage or metastatic patterns were analyzed. There was no difference of mutation frequency and burden according to stage. However, liver metastasis was associated with higher frequency of TP 53 mutation (OR = 3.40; P = 0.010) and mutation burden was significantly lower in the lung metastasis (35.4 vs 50.9; P = 0.023). In the gene-set enrichment analysis using WTS, distinct pathways were observed according to the potential mechanism related with each metastatic pattern. Conclusions: Integrative clinico-genomic analysis of Asian PDA cohort provided various clues to better understand the genomic landscape of PDA.