Pancreatic cancer genomics: insights and opportunities for clinical translation

Abstract

Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are present in all cells of the infiltrating carcinoma, and those that accumulate specifically within the infiltrating carcinoma during subclonal evolution, resulting in genetic heterogeneity. Despite this heterogeneity there are nonetheless commonly altered cellular functions, such as pathways controlling the cell cycle, DNA damage repair, intracellular signaling and development, which could provide for a variety of drug targets. This review aims to summarize current knowledge of the genetics and genomics of pancreatic cancer from its inception to metastatic colonization, and to provide examples of how this information can be translated into the clinical setting for therapeutic benefit and personalized medicine.

Pancreatic cancer

“…The starting point of these lesions occurs in smaller pancreatic ductal cells and can be further classified, depending on the degree of dysplasia [cytonuclear atypia, cell morphology, (in‐) frequent mitosis], into the four grades: 1A, 1B, 2 and 3. The increasing grades of dysplasia in the different PanIN lesions reflect the morphological steps of tumour progression that precede the invasive cancer over time and are genetically accompanied by successive accumulation of mutations, involving activation of the KRAS2 oncogene and inactivation of the tumour suppressor genes TP53 , SMAD4 and CDKN2A (Makohon‐Moore et al ., ; Table ). However, PDAC is by far the most common and most lethal histological subtype.…”

Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

“…Patients face a one-year survival rate of 25% and a 5-year survival rate of only 6% (2). A proposed factor in the limited success of molecular therapies has been the heterogeneity found in pancreatic ductal adenocarcinoma (PDAC) samples pointing toward the need for strategies that target proteins that can affect multiple pathways (3–5). Lack of clinical efficacy is due, in part, to the desmoplastic fibrosis that accompanies pancreatic cancer (6, 7).…”

Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer

“…A number of DNA sequence analyses of tumor samples isolated from large numbers of pancreatic cancer patients indicate that, from the gene mutation perspective, pancreatic cancer is a highly heterogeneous disease, 13 , 15 suggesting that pancreatic cancer cannot be characterized by a narrowly defined set of mutations across all patients. 35 In the present study, we were interested in further examining this question by comparing the most significantly differentially expressed genes/pathways between pancreatic cancer and control samples as determined by group versus personalized analyses of the same samples. Toward this end, we used LCM to collect 3 distinct sets (biological replicates) of normal and cancer cells from tissue samples obtained from 4 pancreatic patients.…”