Poster Presentation 29th Lorne Cancer Conference 2017

Subclonal mutation rate as a marker of risk of invasion in colorectal adenomas (#236)

Benedict Ng 1 , Sameer Srivastava 2 , Peter Zarzour 1 , Mathew A Sloane 1 , Dominik Beck 1 3 , Nicholas J Hawkins 4 , Michael J Bourke 5 , Robyn L Ward 1 4 , Jason WH Wong 1 , Luke B Hesson 1
  1. Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, NSW, Australia
  2. Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
  3. Centre for Health Technologies and the School of Software, University of Technology, Sydney, Ultimo, NSW, Australia
  4. Faculty of Medicine, University of Queensland, Herston, Queensland, Australia
  5. Department of Gastroenterology, Westmead Hospital, Sydney, NSW, Australia

Benign flat colorectal adenomas with a large nodule (mixed morphology) have a greater rate of invasion, especially underneath the nodule. In this study, we examined 5 adenomas of mixed morphology using whole exome sequencing, SNParray, RNA-seq and MBD-seq, in order to discover how flat and nodular tissues differ. We found that flat and nodular tissues have similar mutational burdens and mutational signatures. They also have similar differentially expressed and methylated genes. Furthermore, combining genetic, epigenetic and transcriptional analyses did not reveal any consistent differences between flat and nodular tissues. However, when we examined clonal and subclonal evolution in these adenomas, we found differences in 2 out of the 4 patients studied. Specifically, nodular tissues in Patients 1 and 3 had subclonal architecture compared to a more clonal distribution in corresponding flat tissues. Calculation of subclonal mutation rates using variant allele frequencies (VAFs) showed that nodular tissue had significantly higher mutation rates in 3 out of the 4 adenomas studied (Patients 1, 2 and 3). We propose that this increased subclonal mutation rate in nodular tissues is a marker for how quickly the nodule is growing, and may also underlie their greater invasive potential. We discuss possible mechanisms which may be responsible for increased subclonal mutation rates in some nodular tissues. To our knowledge, this is the first study to find different mutation rates in different parts of the same colorectal adenoma.