PDAC is one of most aggressive human malignancies with clinical characteristics of local invasion, early metastasis, and resistance to standard chemotherapy. The genes involved in inherited pancreatic cancer could be classified into two categories: hereditary tumor predisposition syndromes and syndromes with chronic inflammation of the pancreas( including PRSS1, SPINK1 and CFTR). PRSS1, SPINK1 and CFTR mutation were germline mutations associated with human pancreatitis caused by chronic inflammation. Individuals with PRSS1 or SPINK1 mutation had a very high risk in PDAC, about 50-80 times compared to normal population. The association between germline mutations involved in the pancreatic digestive enzyme with a dramatically increased risk of cancer highlights the importance of chronic injury, inflammation, and repair in the pathogenesis of cancer. Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many cancer types shortly. Combined immunotherapies is potential a direction to treatment PDAC. There is little knowledge about the differences between genetic pancreatitis associated PDAC (GP-PDAC) and sporadic PDAC (S-PDAC). In this project, we plan to dissect the differences the GP-PDAC and S-PDAC in several aspects: clinical characteristics and outcome, genetic alteration, and immune contexture. By understanding this, treatment of PDAC would be to move forward into personalized therapy. Three aims proposed to achieve the goal: Aim 1 To compare the differences in clinical characteristics and outcome of genetic pancreatitis associated pancreatic ductal adenocarcinoma (GP-PDAC) and sporadic pancreatic ductal adenocarcinoma(S-PDAC) in our population Aim 2 To elucidate the genetic mutations and molecular pathway in genetic pancreatitis associated pancreatic ductal adenocarcinoma (GP-PDAC) and sporadic pancreatic ductal adenocarcinoma(S-PDAC) Aim 3 To elucidate the immune contexture and the correlation of immunoscore and outcome/survival in genetic pancreatitis associated pancreatic ductal adenocarcinoma (GP-PDAC) and sporadic pancreatic ductal adenocarcinoma(S-PDAC) In the preliminary study, we detected 26 GP-PDAC in 300 tissue-proved PDAC retrospectively. In age and gender matched stage IV PDAC, we found that GP-PDACs had better survival than sporadic PDACs (mean survival in GP-PDAC 8.1(5.1-10.2)months; S-PDAC: 4.6 (3.1-6.1)months, P<0.05, long rank test). The results from this subproject will help us to understand the differences in cancer cell mutation and immune contexture of GP-PDAC and S-PDAC. The results from this subproject will increase our knowledge of pancreatic carcinogenesis and the immune contexture in a different inflammatory background. The result could potentially enable the development of an early screening marker. Besides, the result would be translated to personalized therapy in pancreatic ducal adenocarcinoma.
pancreatic ductal adenocarcinoma