Phenome-genome association studies of pancreatic cancer: new targets for therapy and diagnosis

Abstract

Background: Pancreatic cancer, has a very high mortality rate and requires novel molecular targets for diagnosis and therapy. Genetic association studies over databases offer an attractive starting point for gene discovery.

Materials and methods: The National Center for Biotechnology Information (NCBI) Phenome Genome Integrator (PheGenI) tool was enriched for pancreatic cancer-associated traits. The genes associated with the trait were characterized using diverse bioinformatics tools for Genome-Wide Association (GWA), transcriptome and proteome profile and protein classes for motif and domain.

Results: Two hundred twenty-six genes were identified that had a genetic association with pancreatic cancer in the human genome. This included 25 uncharacterized open reading frames (ORFs). Bioinformatics analysis of these ORFs identified putative druggable proteins and biomarkers including enzymes, transporters and G-protein-coupled receptor signaling proteins. Secreted proteins including a neuroendocrine factor and a chemokine were identified. Five out of these ORFs encompassed non coding RNAs. The ORF protein expression was detected in numerous body fluids, such as ascites, bile, pancreatic juice, milk, plasma, serum and saliva. Transcriptome and proteome analyses showed a correlation of mRNA and protein expression for nine ORFs. Analysis of the Catalogue of Somatic Mutations in Cancer (COSMIC) database revealed a strong correlation across copy number variations and mRNA over-expression for four ORFs. Mining of the International Cancer Gene Consortium (ICGC) database identified somatic mutations in a significant number of pancreatic patients' tumors for most of these ORFs. The pancreatic cancer-associated ORFs were also found to be genetically associated with other neoplasms, including leukemia, malignant melanoma, neuroblastoma and prostate carcinomas, as well as other unrelated diseases and disorders, such as Alzheimer's disease, Crohn's disease, coronary diseases, attention deficit disorder and addiction.

Conclusion: Based on Genome-Wide Association Studies (GWAS), copy number variations, somatic mutational status and correlation of gene expression in pancreatic tumors at the mRNA and protein level, expression specificity in normal tissues and detection in body fluids, six ORFs emerged as putative leads for pancreatic cancer. These six targets provide a basis for accelerated drug discovery and diagnostic marker development for pancreatic cancer.

Keywords: Alzheimer’s disease; biomarkers; body fluids; clinical variations; dark matter proteome; druggable targets; expression quantitative loci; gene ontology; genome-wide association studies; leukemia and lymphoma; malignant melanoma; neuroblastoma; open reading frames; pancreatic cancer; phenome-genome association.