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Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates
  1. Chelsie K Sievers1,2,
  2. Luli S Zou2,
  3. Perry J Pickhardt3,
  4. Kristina A Matkowskyj4,5,
  5. Dawn M Albrecht2,
  6. Linda Clipson1,
  7. Jeffery W Bacher6,
  8. B Dustin Pooler3,
  9. Fouad J Moawad7,
  10. Brooks D Cash7,8,
  11. Mark Reichelderfer2,
  12. Tien N Vo9,
  13. Michael A Newton9,10,
  14. Bret R Larget9,11,
  15. Richard B Halberg1,2,12
  1. 1Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
  2. 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
  3. 3Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
  4. 4Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
  5. 5US Department of Veterans Affairs, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA
  6. 6Genetic Analysis Group, Promega Corporation, Madison, Wisconsin, USA
  7. 7Gastroenterology Service, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
  8. 8Gastroenterology Division, Department of Medicine, University of South Alabama, Mobile, Alabama, USA
  9. 9Department of Statistics, University of Wisconsin–Madison, Madison, Wisconsin, USA
  10. 10Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, USA
  11. 11Department of Botany, University of Wisconsin–Madison, Madison, Wisconsin, USA
  12. 12Carbone Cancer Center, University of Wisconsin–Madison, Madison, Wisconsin, USA
  1. Correspondence to Dr Richard B Halberg, Room 7533, Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA; rbhalberg{at}medicine.wisc.edu

Abstract

Objective and design The goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour. The growth of small polyps (6–9 mm) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography. Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing. The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness.

Results The mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour. Polyps carried 0–3 pathogenic mutations with the most frequent being in APC, KRAS/NRAS, BRAF, FBXW7 and TP53. In polyps with two or more pathogenic mutations, allele frequencies were often variable, indicating the presence of multiple populations within a single tumour. Based on computer modelling, detectable mutations occurred at a mean polyp size of 30±35 crypts, well before the tumour is of a clinically detectable size.

Conclusions These data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour. Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease.

  • COLORECTAL CANCER
  • COLONIC POLYPS
  • IMAGE ANALYSIS
  • MOLECULAR GENETICS
  • STATISTICS

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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