Leukocyte complexity and the mutational spectrum of periampullary cancer: relationship with morphology and clinical outcome

Introduction Tumours arising in the periampullary region are diverse but share the common trait of having a poor prognosis. Anatomical origins for periampullary adenocarcinomas include the head of the pancreas, the duodenum, the common bile duct and the ampulla of Vater. For pancreatic cancer, the five-year overall survival rate is only 5 %, with a median survival rate of 6 months. Approximately 85% of the patients are diagnosed in an advanced stage, thus not being eligible for curative resection. For patients with resectable disease, morphological subtype is an important prognostic factor, with intestinal-type (I-type) morphology being associated with a better outcome and pancreatobiliary type (PB-type) morphology with a poorer outcome. Although the vast majority of pancreatic cancers contain somatic mutations, there is still a lack of “actionable” molecular targets. Adding to this, pancreatic cancer creates a nonimmunogenic, or “cold”, tumour microenvironment, thus limiting the effects of immunotherapies. Therefore, standard of care treatment for these patients remains limited to conventional cytotoxic chemotherapy, and there is a great need to identify novel treatment strategies and predictive biomarkers for improved treatment. The overarching aim of this thesis project is to map the leukocyte complexity and mutational landscape of periampullary adenocarcinomas, with particular reference to their relationship with morphological type and clinical outcome.