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

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 mi...

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Autores principales: Kim, Tae-Min, An, Chang Hyeok, Rhee, Je-Keun, Jung, Seung-Hyun, Lee, Sung Hak, Baek, In-Pyo, Kim, Min Sung, Lee, Sug Hyung, Chung, Yeun-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695021/
https://www.ncbi.nlm.nih.gov/pubmed/26336987
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author Kim, Tae-Min
An, Chang Hyeok
Rhee, Je-Keun
Jung, Seung-Hyun
Lee, Sung Hak
Baek, In-Pyo
Kim, Min Sung
Lee, Sug Hyung
Chung, Yeun-Jun
author_facet Kim, Tae-Min
An, Chang Hyeok
Rhee, Je-Keun
Jung, Seung-Hyun
Lee, Sung Hak
Baek, In-Pyo
Kim, Min Sung
Lee, Sug Hyung
Chung, Yeun-Jun
author_sort Kim, Tae-Min
collection PubMed
description 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 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.
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spelling pubmed-46950212016-01-20 Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma Kim, Tae-Min An, Chang Hyeok Rhee, Je-Keun Jung, Seung-Hyun Lee, Sung Hak Baek, In-Pyo Kim, Min Sung Lee, Sug Hyung Chung, Yeun-Jun Oncotarget Research Paper 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 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent. Impact Journals LLC 2015-08-07 /pmc/articles/PMC4695021/ /pubmed/26336987 Text en Copyright: © 2015 Kim et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kim, Tae-Min
An, Chang Hyeok
Rhee, Je-Keun
Jung, Seung-Hyun
Lee, Sung Hak
Baek, In-Pyo
Kim, Min Sung
Lee, Sug Hyung
Chung, Yeun-Jun
Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title_full Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title_fullStr Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title_full_unstemmed Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title_short Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
title_sort clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695021/
https://www.ncbi.nlm.nih.gov/pubmed/26336987
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