Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma

Oncotarget
Tae-Min KimYeun-Jun Chung

Abstract

Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four-stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a 'parallel' evolution of synchronous adenoma-to-carcinoma, rather than a 'stepwise' evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplifi...Continue Reading

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Citations

Jun 11, 2016·The Journal of Pathology·William Ch CrossNicholas A Wright
Oct 23, 2019·International Journal of Molecular Sciences·Adewale Oluwaseun FadakaAshwil Klein
Jul 28, 2016·Einstein·Guilherme Muniz BourroulJaques Waisberg
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Methods Mentioned

BETA
exome sequencing
dissection

Software Mentioned

SomaticIndelDetector
IGV
Mutect
ANNOVAR
Samtools
dbscan
Genome Analysis ToolKit
VarScan2

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