Chapter 138: Molecular Genetics of Pancreatic Neoplasms and Inherited Pancreatic Cancer Syndromes

INTRODUCTION

Cancer is fundamentally a genetic disease that develops when alterations in multiple genes result in dysregulation of a select number of cellular pathways and processes. In the last decade, rapid advances in nucleotide sequencing and bioinformatic technology have led to an expansion of information obtained from the sequencing of cancer genomes. Sequencing of pancreatic cancer (PC) genomes as well as premalignant lesions of the pancreas has deepened our understanding of tumorigenesis and identified potential novel therapeutic targets. Although PC has generally been associated with acquired genetic mutations, a small proportion of PCs may be due to inherited PC syndromes. In this chapter, we focus on the current understanding of proposed critical genes and affected pathways that have been shown to be important in sporadic and hereditary PCs.

PANCREATIC CANCER GENOMES

With the rapid advancement of next generation sequencing technology, several cancer sequencing initiatives have focused on characterizing the genomic landscape of PC. The first genome-wide analysis of PC was performed in 2008, based on 24 pancreatic tumors and xenografts using capillary sequencing and single nucleotide polymorphism arrays.¹ This study found that PCs harbor, on average, 48 genetic mutations and confirmed that KRAS, TP53, CDKN2A, and SMAD4 were the most commonly mutated genes in this disease. Despite the large number of mutations, if one excludes KRAS, TP53, CDKN2A, and SMAD4,² none of the remaining mutated genes occurred with a prevalence greater than 5%. However, the authors were able to classify these genes into 12 core signaling pathways, which they suggested could be potential targets for therapeutic interventions. A subsequent study that utilized whole exome sequencing and copy-number analysis of 99 human PCs confirmed the vast heterogeneity of mutated genes. This study was remarkable for the use of laser capture microdissection of the pancreatic tumors to minimize the incorporation of stromal elements and maximize the enrichment of the sample for adenocarcinoma. This study identified 2,016 genes with nonsilent mutations and 1,628 copy-number variations, with an average of 26 mutations per patient. In addition to KRAS, TP53, CDKN2A, and SMAD4, mutations in several novel genes including ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6, EPC1, and ATM were identified. These mutations identified novel pathways not originally identified in the previous 12 core signaling pathways, which affect chromatin modification and axon-guidance. Similar to previous reports, the investigators also demonstrated that the majority of mutated genes had a prevalence of less than 2%. Although PC has generally been associated with acquired genetic mutations, a small proportion of PCs may be due to inherited PC syndromes. In this chapter, we focus on the current understanding of proposed critical genes and affected pathways that have been shown to be important in sporadic and hereditary PCs.³ The integrated genomic and transcriptional analysis further refined the biological insights into PC pathogenesis and may help to ...