Poster Presentation 29th Lorne Cancer Conference 2017

Identification of clinically relevant colon cancer genes predictive of improved relapse free survival (#246)

Marie Parsons 1 2 , Dmitri Mouradov 3 , Robyn Ward 4 , Oliver Sieber 3
  1. Department of Surgery, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. Systems Biology and Personalised Medicine Division, Walter and Eliza Hall of Medical Research, Melbourne, VIC, Australia
  4. Office of Vice Chancellor (Research), University of Queensland, Brisbane, Queensland

Colorectal cancer (CRC) is the third most common cancer worldwide, affecting over 15,000 individuals in Australia each year. While CRC is often detected at a stage where resection of the primary tumour is possible, approximately 50% will relapse and die from metastatic disease. Prognostication is mainly determined by tumour depth (T), lymph node stage (N) and the extent of cancer spread (M). However, clinical outcomes of patients with the same TNM stage can be heterogeneous. Therefore, there is a need to identify markers to better predict prognosis and stratify patients for treatment regimes.

 

A panel of 113 candidate CRC genes were identified as significantly mutated in whole genome and whole exome sequencing studies from 361 MSS colon cancers and 63 CRC cell lines. Custom amplicon panels for target enrichment were designed for use with the HaloPlexTM target enrichment system. Sample libraries were prepared for 274 patients with stage II/III CRC using the automated Bravo liquid handling platform and next-generation sequencing (NGS) on the Illumina Next-Seq 500.

 

Analysis of the 113 candidate genes identified 31 genes recurrently mutated above 10 percent in our discovery cohort. We identified 4 genes previously reported as colon cancer genes (APC 68%, TP53 60%, KRAS 30% and PIK3CA 20%), confirming APC, TP53 and KRAS as the most frequently mutated genes in CRC. To identify novel and clinically relevant genes, the 31 genes in our discovery cohort were tested for association with clinical features of CRC. In the discovery cohort, 24/31 genes were significantly associated with right sided CRC, 10/31 with mucinous CRC, 9/31 with stage II CRC and 7/31 with improved relapse free survival (RFS). Of these significantly associated genes, 10/24 genes were validated as significantly associated with right sided colon cancer, 3/9 with stage II and 3/10 with mucinous CRC in the validation cohort. Five of these genes were selected for further investigation as they were significantly associated with improved RFS and one or more clinical feature of CRC.

 

Identification of novel recurrently mutated genes is key to a better understanding of the molecular mechanisms of CRC and development of novel therapeutics.