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Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling
BACKGROUND: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge. METHODS: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076308/ https://www.ncbi.nlm.nih.gov/pubmed/33658639 http://dx.doi.org/10.1038/s41416-021-01266-4 |
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author | Yaegashi, Mizunori Iwaya, Takeshi Sasaki, Noriyuki Fujita, Masashi Ju, Zhenlin Siwak, Doris Hachiya, Tsuyoshi Sato, Kei Endo, Fumitaka Kimura, Toshimoto Otsuka, Koki Sugimoto, Ryo Sugai, Tamotsu Liotta, Lance Lu, Yiling Mills, Gordon B. Nakagawa, Hidewaki Nishizuka, Satoshi S. |
author_facet | Yaegashi, Mizunori Iwaya, Takeshi Sasaki, Noriyuki Fujita, Masashi Ju, Zhenlin Siwak, Doris Hachiya, Tsuyoshi Sato, Kei Endo, Fumitaka Kimura, Toshimoto Otsuka, Koki Sugimoto, Ryo Sugai, Tamotsu Liotta, Lance Lu, Yiling Mills, Gordon B. Nakagawa, Hidewaki Nishizuka, Satoshi S. |
author_sort | Yaegashi, Mizunori |
collection | PubMed |
description | BACKGROUND: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge. METHODS: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples. RESULTS: “Founder” mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, “truncal” mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than “non-founder” and “branch” mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring. CONCLUSIONS: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours. |
format | Online Article Text |
id | pubmed-8076308 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-80763082021-05-05 Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling Yaegashi, Mizunori Iwaya, Takeshi Sasaki, Noriyuki Fujita, Masashi Ju, Zhenlin Siwak, Doris Hachiya, Tsuyoshi Sato, Kei Endo, Fumitaka Kimura, Toshimoto Otsuka, Koki Sugimoto, Ryo Sugai, Tamotsu Liotta, Lance Lu, Yiling Mills, Gordon B. Nakagawa, Hidewaki Nishizuka, Satoshi S. Br J Cancer Article BACKGROUND: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge. METHODS: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples. RESULTS: “Founder” mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, “truncal” mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than “non-founder” and “branch” mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring. CONCLUSIONS: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours. Nature Publishing Group UK 2021-03-03 2021-04-27 /pmc/articles/PMC8076308/ /pubmed/33658639 http://dx.doi.org/10.1038/s41416-021-01266-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yaegashi, Mizunori Iwaya, Takeshi Sasaki, Noriyuki Fujita, Masashi Ju, Zhenlin Siwak, Doris Hachiya, Tsuyoshi Sato, Kei Endo, Fumitaka Kimura, Toshimoto Otsuka, Koki Sugimoto, Ryo Sugai, Tamotsu Liotta, Lance Lu, Yiling Mills, Gordon B. Nakagawa, Hidewaki Nishizuka, Satoshi S. Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title | Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title_full | Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title_fullStr | Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title_full_unstemmed | Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title_short | Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling |
title_sort | frequent post-operative monitoring of colorectal cancer using individualised ctdna validated by multiregional molecular profiling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076308/ https://www.ncbi.nlm.nih.gov/pubmed/33658639 http://dx.doi.org/10.1038/s41416-021-01266-4 |
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