Poster Presentation 25th Lorne Cancer Conference 2013

A Single Transcriptional Program Underpins Patient Survival in Pancreatic Cancer (#312)

Mark Pinese 1 , Mark J Cowley 1 , Jianmin Wu 1 , Marc D Jones 1 , Katia Nones 2 , Andrew V Biankin 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, Brisbane, QLD, Australia

Introduction:

Patients with pancreatic cancer display a wide range of survival times post diagnosis, but the reasons for much of this variability remain unknown. We reasoned that examination of the transcriptional state of individual cancers would provide insight into the biological processes underlying patient survival, enabling better staging and indicating new therapeutic avenues. To this end we aimed to identify transcriptional programs that predicted patient survival in resected pancreatic cancer.

Methods and Results:

As part of the Australian Pancreatic Cancer Genome Initiative, 94 bulk resected pancreatic cancer samples, with full clinical data, were arrayed on Illumina HumanHT-12 v3 chips. Following analysis, 542 genes were identified as individually being associated with patient survival; these were transformed by PCA to 10 metagenes. Only the first metagene, PC1, was significantly associated with patient outcome following cross-validation. PC1 was not associated with estimates of tumour stromal content, clinico-pathological variables, or cell proliferation signatures, and remained strongly prognostic in a full model including all commonly-used clinical-pathological variables.

We performed over-representation analysis to identify a putative biological significance behind PC1, and found that PC1 was significantly enriched for 198 MSigDB gene sets. To reduce this number of sets for interpretability, we developed a novel meta-signature technique that indicated that PC1 was not a conventional cancer signature, but was instead encoding information on hypoxia/EGF vs immune response. Ongoing work is investigating links between PC1 and tissue stiffness, perfusion, and immune availability.

Summary:

We have identified a single major metagene, PC1, that underpins much of the previously-unexplained variability in survival time of patients with pancreatic cancer. PC1 encodes information on a tumour's hypoxic state vs immune involvement, and its importance highlights the role of the tumour environment in pancreatic cancer. Links between PC1 and tissue stiffness, which is pharmacologically targetable, reveals a new therapeutic avenue for this dire cancer.