Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer

Background Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were de...

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Published in:British journal of cancer 2023-08, Vol.129 (2), p.374-381
Main Authors: Ryoo, Seung-Bum, Heo, Sunghoon, Lim, Yoojoo, Lee, Wookjae, Cho, Su Han, Ahn, Jongseong, Kang, Jun-Kyu, Kim, Su Yeon, Kim, Hwang-Phill, Bang, Duhee, Kang, Sung-Bum, Yu, Chang Sik, Oh, Seong Taek, Park, Ji Won, Jeong, Seung-Yong, Kim, Young-Joon, Park, Kyu Joo, Han, Sae-Won, Kim, Tae-You
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692/4028/67/1504/1885/1393
692/4028/67/1504/1885/1777
692/53/2422
Bioassays
Biomarkers, Tumor - genetics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Circulating Tumor DNA - genetics
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - diagnosis
Colorectal Neoplasms - genetics
Deoxyribonucleic acid
Disease-Free Survival
DNA
Drug Resistance
Epidemiology
Humans
Minimal residual disease
Molecular Medicine
Mutation
Neoplasm, Residual - genetics
Oncology
Patients
Tumors
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cited_by cdi_FETCH-LOGICAL-c475t-a8ec298b0992e67b0360c10abed7cc8550fee42cefeffcc00166fede8da9dfaa3
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container_end_page 381
container_issue 2
container_start_page 374
container_title British journal of cancer
container_volume 129
creator Ryoo, Seung-Bum
Heo, Sunghoon
Lim, Yoojoo
Lee, Wookjae
Cho, Su Han
Ahn, Jongseong
Kang, Jun-Kyu
Kim, Su Yeon
Kim, Hwang-Phill
Bang, Duhee
Kang, Sung-Bum
Yu, Chang Sik
Oh, Seong Taek
Park, Ji Won
Jeong, Seung-Yong
Kim, Young-Joon
Park, Kyu Joo
Han, Sae-Won
Kim, Tae-You
description Background Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). Results In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (
doi_str_mv 10.1038/s41416-023-02300-3
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We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). Results In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (&lt;0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49–20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS ( P  &lt; 0.001). Conclusion Tumour-informed, hybrid-capture-based ctDNA assay monitoring a large number of patient-specific mutations is a sensitive strategy for MRD detection to predict recurrence in CRC.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/s41416-023-02300-3</identifier><identifier>PMID: 37280413</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/4028/67/1504/1885/1393 ; 692/4028/67/1504/1885/1777 ; 692/53/2422 ; Bioassays ; Biomarkers, Tumor - genetics ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Circulating Tumor DNA - genetics ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - diagnosis ; Colorectal Neoplasms - genetics ; Deoxyribonucleic acid ; Disease-Free Survival ; DNA ; Drug Resistance ; Epidemiology ; Humans ; Minimal residual disease ; Molecular Medicine ; Mutation ; Neoplasm, Residual - genetics ; Oncology ; Patients ; Tumors</subject><ispartof>British journal of cancer, 2023-08, Vol.129 (2), p.374-381</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-a8ec298b0992e67b0360c10abed7cc8550fee42cefeffcc00166fede8da9dfaa3</citedby><cites>FETCH-LOGICAL-c475t-a8ec298b0992e67b0360c10abed7cc8550fee42cefeffcc00166fede8da9dfaa3</cites><orcidid>0000-0003-3275-431X ; 0000-0003-0046-8175 ; 0000-0001-6407-0444 ; 0000-0001-5220-0352</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338477/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338477/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,730,783,787,888,27936,27937,53804,53806</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37280413$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ryoo, Seung-Bum</creatorcontrib><creatorcontrib>Heo, Sunghoon</creatorcontrib><creatorcontrib>Lim, Yoojoo</creatorcontrib><creatorcontrib>Lee, Wookjae</creatorcontrib><creatorcontrib>Cho, Su Han</creatorcontrib><creatorcontrib>Ahn, Jongseong</creatorcontrib><creatorcontrib>Kang, Jun-Kyu</creatorcontrib><creatorcontrib>Kim, Su Yeon</creatorcontrib><creatorcontrib>Kim, Hwang-Phill</creatorcontrib><creatorcontrib>Bang, Duhee</creatorcontrib><creatorcontrib>Kang, Sung-Bum</creatorcontrib><creatorcontrib>Yu, Chang Sik</creatorcontrib><creatorcontrib>Oh, Seong Taek</creatorcontrib><creatorcontrib>Park, Ji Won</creatorcontrib><creatorcontrib>Jeong, Seung-Yong</creatorcontrib><creatorcontrib>Kim, Young-Joon</creatorcontrib><creatorcontrib>Park, Kyu Joo</creatorcontrib><creatorcontrib>Han, Sae-Won</creatorcontrib><creatorcontrib>Kim, Tae-You</creatorcontrib><title>Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). Results In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (&lt;0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49–20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS ( P  &lt; 0.001). 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We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). Results In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (&lt;0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49–20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS ( P  &lt; 0.001). Conclusion Tumour-informed, hybrid-capture-based ctDNA assay monitoring a large number of patient-specific mutations is a sensitive strategy for MRD detection to predict recurrence in CRC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37280413</pmid><doi>10.1038/s41416-023-02300-3</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-3275-431X</orcidid><orcidid>https://orcid.org/0000-0003-0046-8175</orcidid><orcidid>https://orcid.org/0000-0001-6407-0444</orcidid><orcidid>https://orcid.org/0000-0001-5220-0352</orcidid><oa>free_for_read</oa></addata></record>
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subjects 692/4028/67/1504/1885/1393
692/4028/67/1504/1885/1777
692/53/2422
Bioassays
Biomarkers, Tumor - genetics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Circulating Tumor DNA - genetics
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - diagnosis
Colorectal Neoplasms - genetics
Deoxyribonucleic acid
Disease-Free Survival
DNA
Drug Resistance
Epidemiology
Humans
Minimal residual disease
Molecular Medicine
Mutation
Neoplasm, Residual - genetics
Oncology
Patients
Tumors
title Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer
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