Genetic and molecular alterations in pancreatic cancer progression by next generation sequencing

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human pancreatic cancer type accounting for about 90% of all malignant pancreatic neoplasms. It represents the fourth leading cause of cancer death in the Western World, projected to become the second cause by 2030. In our country, the PDAC incidence is about 14,000 new cases per year and represents 3% of all cancer cases (AIRTUM 2019), equally distributed between the sexes. Up to 15-20% of patients are eligible for resection at diagnosis. The 5 years overall survival for PDAC patients is around 8%; even for patients eligible for resection, the 5 years survival is no more than 15-20%. At least 25% of pancreatic cancers harbor "actionable" molecular alterations, defined as molecular alterations for which there is clinical evidence of a predictive benefit from a specific therapy (targeted therapy). We started a study by Next Generation Sequencing (NGS) analysis in primitive and metastatic PDAC tissues from the same patients, to define the molecular alterations pattern underlying neoplastic progression in pancreatic cancer. Tumor samples - 50 primitive PDAC cases and 50 related lymph node metastases - have been selected from archived formalin-fixed and paraffin-embedded (FFPE) samples, of which clinical-pathological data are available. To date have been analyzed 11 samples (4 primitive/metastasis matched cases and 3 primitive tumors) by NGS screening using "Oncomine Tumor specific panel", including main genes involved in onset and progression of PDAC (KRAS, CDKN2A, SMAD4, CHEK2, APC, NF1), in genome damage repair (POLE, PALB2, PTEN, TP53), and in mismatch repair mechanism (MLH1, MSH2.MSH3, MSH6). Preliminary data of mutational analysis are shown in the following Tables. The main endpoint for the analysis of all of cases is to identify mutational patterns to relate to clinical-pathological parameters of PDAC, as a starting point for finding novel tumor biomarkers associated with the disease.