Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates.
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.



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 inAPC,KRAS/NRAS,BRAF,FBXW7andTP53. 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.



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.
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Chelsie K
CK
Sievers
Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Luli S
LS
Zou
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Perry J
PJ
Pickhardt
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|US Department of Veterans Affairs, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
Kristina A
KA
Matkowskyj
Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Dawn M
DM
Albrecht
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Linda
L
Clipson
Genetic Analysis Group, Promega Corporation, Madison, Wisconsin, USA.
Jeffery W
JW
Bacher
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
B Dustin
BD
Pooler
Gastroenterology Service, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
Fouad J
FJ
Moawad
Gastroenterology Service, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.|Gastroenterology Division, Department of Medicine, University of South Alabama, Mobile, Alabama, USA.
Brooks D
BD
Cash
Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Mark
M
Reichelderfer
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Tien N
TN
Vo
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Michael A
MA
Newton
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Botany, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Bret R
BR
Larget
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Richard B
RB
Halberg
D000483:Alleles; D002471:Cell Transformation, Neoplastic; D003111:Colonic Polyps / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D023881:Colonography, Computed Tomographic; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype
COLONIC POLYPS; COLORECTAL CANCER; IMAGE ANALYSIS; MOLECULAR GENETICS; STATISTICS