Comprehensive clinico-genomic analysis of pancreatic ductal adenocarcinoma: Overcoming biases and limitations

Pancreatic ductal adenocarcinoma (PDAC) has an exceptionally poor prognosis. Most genomic studies conducted to discover potential targets to improve PDAC prognosis have been constrained by biased cohort compositions and limited clinical information. Therefore, we aimed to develop a large-scale, unbiased, and well-organized PDAC genomic dataset. Primary pancreatic tissue samples were exclusively obtained from patients with PDAC using endoscopic ultrasound-guided fine-needle biopsy, and whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were conducted. Subsequently, comprehensive clinico-genomic analysis was performed by integrating this genomic dataset with detailed clinical information. A unique and unbiased genomic dataset, comprising 205 WES and 93 WTS datasets from 237 Asian patients with PDAC, was developed. The clinico-genomic analysis revealed distinct genetic features associated with various clinical phenotypes. Specifically, patients with liver metastasis exhibited a high frequency of TP53 mutation, increased chromosomal instability, and high frequency of copy number variants as well as KRAS allelic imbalance. Additionally, potential biomarkers derived from broad genomic data, including tumor mutation burden, mutation signatures, scar-based homologous recombination deficiency signatures, and RNA subtypes, were validated for their clinical utility. This large-scale, unbiased genomic dataset addresses the limitations of previous genomic studies in PDAC, facilitating comprehensive clinico-genomic analyses with significant clinical utility.