Genomic Landscape of Pancreatic Adenocarcinoma in Younger vs Older Patients: Does Age Matter?

Purpose: State-of the art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine if early-onset PDAC (EOPC; ≤ 55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥ 70 years). Experimental Design: Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering (MSK) were consented for MSK-IMPACT next generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression and protein expression. The third dataset was an Australian cohort of PDAC. Clinical data were correlated with genomic analyses. Results: Two hundred and ninety-three samples were analyzed, yielding 90 patients (pts) aged ≤ 55 years and 203 pts aged ≥ 70 years. Among the genes known to be associated with carcinogenesis SMAD4 displayed higher mutation rates in younger patients. Comprehensive transcriptomic analysis of cellular pathways indicated that the TGFb pathway has increased activation and the expression levels of phospo-GSK3 were higher in EOPC. Survival outcomes revealed no differences between age groups. Conclusions: These exploratory analyses suggest that there may be somatic gene alterations within the population of early onset PDAC patients that involve unique cellular pathways compared with average onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future evaluation to extend these observations.

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