Understanding the Genetics of Pancreatic Adenocarcinoma

Abstract

The underlying molecular basis of pancreatic ductal adenocarcinoma (PDAC) is complex, with multiple genetic, epigenetic, and transcriptomic changes. Five to 10% of PDAC cases have a hereditary basis, with multiple risk-conferring genetic mutations running in the family. All PDAC tumors develop from noninvasive precursor lesions that reflect the temporal accumulation of mutations. Recent advances in high-throughput sequencing technologies have facilitated a better understanding of the diverse mutational landscape of PDAC, reaffirming the role of genes previously known to be mutated (K-ras, CDKN2A, TP53, SMAD4, SLIT/ROBO, SWI/SNF) and revealing novel insights into the differential gene expression patterns and structural variations involved. K-ras mutation, an early event in disease pathogenesis, plays a pivotal role in the initiation, progression, and maintenance of PDAC, with the mutation type impacting disease pathophysiology and prognosis. The subsequent loss of tumor suppressors (CDKN2A, TP53, SMAD4) promotes genetic instability and uncontrolled cellular proliferation. Molecular subtypes with potential prognostic and therapeutic relevance have been identified. The challenge now is to translate this wealth of knowledge to the clinic. This review contains 3 figures, 3 tables and 50 references Key words: familial pancreatic cancer, heterogeneity, molecular subtypes, pancreatic ductal adenocarcinoma, whole genome/exome sequencing