RT Journal Article
SR Electronic
T1 Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2132
OP 2140
DO 10.1136/gutjnl-2016-312232
VO 66
IS 12
A1 Chelsie K Sievers
A1 Luli S Zou
A1 Perry J Pickhardt
A1 Kristina A Matkowskyj
A1 Dawn M Albrecht
A1 Linda Clipson
A1 Jeffery W Bacher
A1 B Dustin Pooler
A1 Fouad J Moawad
A1 Brooks D Cash
A1 Mark Reichelderfer
A1 Tien N Vo
A1 Michael A Newton
A1 Bret R Larget
A1 Richard B Halberg
YR 2017
UL http://gut.bmj.com/content/66/12/2132.abstract
AB 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.