High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies
Abstract Background Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating t...
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| Veröffentlicht in: | Clinical chemistry (Baltimore, Md.) Md.), 2020-04, Vol.66 (4), p.606-613 |
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| creator | Silveira, Amanda Bortolini Bidard, François-Clément Kasperek, Amélie Melaabi, Samia Tanguy, Marie-Laure Rodrigues, Manuel Bataillon, Guillaume Cabel, Luc Buecher, Bruno Pierga, Jean-Yves Proudhon, Charlotte Stern, Marc-Henri |
| description | Abstract
Background
Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool.
Methods
We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy.
Results
The 3 ddPCR assays reached analytical sensitivity |
| doi_str_mv | 10.1093/clinchem/hvaa013 |
| format | Article |
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Background
Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool.
Methods
We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy.
Results
The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response.
Conclusions
This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses.</description><identifier>ISSN: 0009-9147</identifier><identifier>EISSN: 1530-8561</identifier><identifier>DOI: 10.1093/clinchem/hvaa013</identifier><identifier>PMID: 32176763</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Activin ; Assaying ; Biomarkers ; Body fluids ; Cancer ; Colorectal cancer ; Deoxyribonucleic acid ; DNA ; Endometrial cancer ; Endometrium ; Gastrointestinal diseases ; Genetic markers ; Immunotherapy ; Life Sciences ; Microsatellite instability ; Microsatellites ; Monitoring ; Patients ; Telemedicine ; Tumors</subject><ispartof>Clinical chemistry (Baltimore, Md.), 2020-04, Vol.66 (4), p.606-613</ispartof><rights>American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com 2020</rights><rights>American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.</rights><rights>COPYRIGHT 2020 American Association for Clinical Chemistry, Inc.</rights><rights>American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-d44c7ad1517cdfcb7b693baae13f31a8dfc1117d9e98bb93227b0be508b85f2e3</citedby><cites>FETCH-LOGICAL-c476t-d44c7ad1517cdfcb7b693baae13f31a8dfc1117d9e98bb93227b0be508b85f2e3</cites><orcidid>0000-0002-8100-2272 ; 0000-0002-4649-4574 ; 0000-0001-5932-8949 ; 0000-0002-3952-4296 ; 0000-0003-0903-6803 ; 0000-0002-5443-0802 ; 0000-0002-2863-9995</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32176763$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-03034635$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Silveira, Amanda Bortolini</creatorcontrib><creatorcontrib>Bidard, François-Clément</creatorcontrib><creatorcontrib>Kasperek, Amélie</creatorcontrib><creatorcontrib>Melaabi, Samia</creatorcontrib><creatorcontrib>Tanguy, Marie-Laure</creatorcontrib><creatorcontrib>Rodrigues, Manuel</creatorcontrib><creatorcontrib>Bataillon, Guillaume</creatorcontrib><creatorcontrib>Cabel, Luc</creatorcontrib><creatorcontrib>Buecher, Bruno</creatorcontrib><creatorcontrib>Pierga, Jean-Yves</creatorcontrib><creatorcontrib>Proudhon, Charlotte</creatorcontrib><creatorcontrib>Stern, Marc-Henri</creatorcontrib><title>High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies</title><title>Clinical chemistry (Baltimore, Md.)</title><addtitle>Clin Chem</addtitle><description>Abstract
Background
Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool.
Methods
We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy.
Results
The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response.
Conclusions
This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses.</description><subject>Activin</subject><subject>Assaying</subject><subject>Biomarkers</subject><subject>Body fluids</subject><subject>Cancer</subject><subject>Colorectal cancer</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Endometrial cancer</subject><subject>Endometrium</subject><subject>Gastrointestinal diseases</subject><subject>Genetic markers</subject><subject>Immunotherapy</subject><subject>Life Sciences</subject><subject>Microsatellite instability</subject><subject>Microsatellites</subject><subject>Monitoring</subject><subject>Patients</subject><subject>Telemedicine</subject><subject>Tumors</subject><issn>0009-9147</issn><issn>1530-8561</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNqFkc1v1DAQxS0EokvhzglF4gKCUDuOY_u4bIFdaRESHwdOlu1MNq6SOI2dlv3vcZVtD1w42R79ZuY9P4ReEvyBYEkvbOcG20J_0d5ojQl9hFaEUZwLVpHHaIUxlrkkJT9Dz0K4Ss-Si-opOqMF4RWv6Ar93rpDm6-tnSdtj9klRJh6N-jo_JD5Jvvq7OSDjtB1LkK2G0LUxqX7Mdv4fkyc6SC7dbHN9u56dnX20fkxOAjP0ZNGdwFenM5z9Ovzp5-bbb7_9mW3We9zW_Iq5nVZWq5rwgi3dWMNN5WkRmsgtKFEi1QjhPBaghTGSFoU3GADDAsjWFMAPUfvl7mt7tQ4uV5PR-W1U9v1XrkhJD8KU0zLirIbkvA3Cz5O_nqGEFXvgk329AB-DqqgXGDMqZAJff0PeuXnaUhmVMFYKQWppEjU24U66A7SQuuHCH_iQc8hqN2P72pdUcGSB1EkFi_s3aeGCZoHwQSru0TVfaLqlGhqeXUSMZse6oeG-wgT8G4B_Dz-f9xfoJWt5Q</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Silveira, Amanda 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Determination of Microsatellite Instability Compatible with Liquid Biopsies</title><author>Silveira, Amanda Bortolini ; Bidard, François-Clément ; Kasperek, Amélie ; Melaabi, Samia ; Tanguy, Marie-Laure ; Rodrigues, Manuel ; Bataillon, Guillaume ; Cabel, Luc ; Buecher, Bruno ; Pierga, Jean-Yves ; Proudhon, Charlotte ; Stern, Marc-Henri</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-d44c7ad1517cdfcb7b693baae13f31a8dfc1117d9e98bb93227b0be508b85f2e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Activin</topic><topic>Assaying</topic><topic>Biomarkers</topic><topic>Body fluids</topic><topic>Cancer</topic><topic>Colorectal cancer</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Endometrial cancer</topic><topic>Endometrium</topic><topic>Gastrointestinal diseases</topic><topic>Genetic markers</topic><topic>Immunotherapy</topic><topic>Life 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Clinical chemistry (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silveira, Amanda Bortolini</au><au>Bidard, François-Clément</au><au>Kasperek, Amélie</au><au>Melaabi, Samia</au><au>Tanguy, Marie-Laure</au><au>Rodrigues, Manuel</au><au>Bataillon, Guillaume</au><au>Cabel, Luc</au><au>Buecher, Bruno</au><au>Pierga, Jean-Yves</au><au>Proudhon, Charlotte</au><au>Stern, Marc-Henri</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies</atitle><jtitle>Clinical chemistry (Baltimore, Md.)</jtitle><addtitle>Clin Chem</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>66</volume><issue>4</issue><spage>606</spage><epage>613</epage><pages>606-613</pages><issn>0009-9147</issn><eissn>1530-8561</eissn><abstract>Abstract
Background
Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool.
Methods
We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy.
Results
The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response.
Conclusions
This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>32176763</pmid><doi>10.1093/clinchem/hvaa013</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-8100-2272</orcidid><orcidid>https://orcid.org/0000-0002-4649-4574</orcidid><orcidid>https://orcid.org/0000-0001-5932-8949</orcidid><orcidid>https://orcid.org/0000-0002-3952-4296</orcidid><orcidid>https://orcid.org/0000-0003-0903-6803</orcidid><orcidid>https://orcid.org/0000-0002-5443-0802</orcidid><orcidid>https://orcid.org/0000-0002-2863-9995</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current) |
| subjects | Activin Assaying Biomarkers Body fluids Cancer Colorectal cancer Deoxyribonucleic acid DNA Endometrial cancer Endometrium Gastrointestinal diseases Genetic markers Immunotherapy Life Sciences Microsatellite instability Microsatellites Monitoring Patients Telemedicine Tumors |
| title | High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies |
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