Background:
There is a growing and pressing demand to comprehensively understand the molecular mechanisms underlying cancer driver mutation acquisition during Pancreatic Ductal Adenocarcinoma (PAAD) progression1-2. Many of the existing studies are either underpowered, relying on exome sequencing or on single-stage tumour sample. This study seeks to breakthrough these limitations of contemporary oncology3-5 for PAAD by leveraging a large whole-genome sequencing atlas to investigate genomic events at play during disease onset and progression.
Method:
To enable comprehensive molecular characterisation, we have created a large harmonised genomic atlas of premalignant, primary and metastatic tumour genomes. We have included whole-genome samples from both publicly available data sources (ICGC6, APGI and PCAWG7) and in-house PAAD sequencing efforts at UMCCR. This cohort is systematically analysed through the best-practice bioinformatics pipeline and tools to detect recurrent driver mutations (coding and noncoding) and common mutational signatures in clinically significant segments of the PAAD cohort, including KRAS-mutant and KRAS-wildtype tumours. The recurrent mutations within KRAS-mutant cohort were then stratified through matched tumour samples from different stages to determine whether these arise in premalignant lesions, primary resected tumours or sub-clonal events.
Results:
In conjunction with classic known instigators of premalignant PAAD progression8-10, we have identified additional set of 30+ genes that are involved in key oncogenic pathways involved in PAAD progression in KRAS-mutant cohort. With a bigger sample number, we were able to resolve limitations of previous studies11 by discovering oncogenic events (gain of function mutations, fusions and amplifications) in key genes including BRAF, KRAS, RAF1, ERK, involved in MAPK signalling pathway. Further, the extended list of driver genes attracts highly impactful mutations at low prevalence (1-5% of patients) that were detected through additional genomic changes of key tumour suppressor and oncogenes, often caused by genomic catastrophes. These findings explain how additional components of these core signalling pathways12 suffer low frequency but impactful mutations to promote PAAD, ultimately resulting in heterogeneity in clinical outcomes.
Conclusion:
This study provides deeper understanding of the molecular aetiology of PAAD by providing an accurate map of cancer driving mutations and their relative accrual during PAAD progression which is essential for optimal therapeutic targeting.