The molecular landscape of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.

Keywords: Biomarker; Circulating tumour DNA; Molecular subtypes; PDAC; Somatic mutations.