Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors
Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses...
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| Veröffentlicht in: | Clinical and translational gastroenterology 2020-03, Vol.11 (3), p.e00149-e00149 |
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| creator | Lee, Minyi Eng, George Barbari, Stephanie R. Deshpande, Vikram Shcherbakova, Polina V. Gala, Manish K. |
| description | Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC).
We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations.
Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations.
Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC. |
| doi_str_mv | 10.14309/ctg.0000000000000149 |
| format | Article |
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We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations.
Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations.
Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.</description><identifier>ISSN: 2155-384X</identifier><identifier>EISSN: 2155-384X</identifier><identifier>DOI: 10.14309/ctg.0000000000000149</identifier><identifier>PMID: 32352724</identifier><language>eng</language><publisher>United States: Wolters Kluwer</publisher><subject>Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - genetics ; BRCA1 Protein - genetics ; BRCA2 Protein - genetics ; Clinical Decision-Making - methods ; Colorectal cancer ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Datasets as Topic ; DNA Mismatch Repair - drug effects ; DNA Mismatch Repair - genetics ; DNA Mutational Analysis - methods ; DNA Polymerase II - genetics ; Drug Resistance, Neoplasm - genetics ; Endometrial cancer ; Endometrial Neoplasms - drug therapy ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - pathology ; Exome Sequencing ; Female ; Genomes ; Genomics ; Humans ; Immunotherapy ; Male ; Metadata ; Metastasis ; Microsatellite Instability ; Microsatellite Repeats - genetics ; Mutation ; Poly-ADP-Ribose Binding Proteins - genetics ; Precision medicine ; Recombinational DNA Repair - drug effects ; Recombinational DNA Repair - genetics ; Tumors</subject><ispartof>Clinical and translational gastroenterology, 2020-03, Vol.11 (3), p.e00149-e00149</ispartof><rights>Wolters Kluwer</rights><rights>2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4841-8e74bd4ce00899901ec9be13afaa99b752264cc6297b2299b6c9c9c06707e0d73</citedby><cites>FETCH-LOGICAL-c4841-8e74bd4ce00899901ec9be13afaa99b752264cc6297b2299b6c9c9c06707e0d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145036/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145036/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32352724$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Minyi</creatorcontrib><creatorcontrib>Eng, George</creatorcontrib><creatorcontrib>Barbari, Stephanie R.</creatorcontrib><creatorcontrib>Deshpande, Vikram</creatorcontrib><creatorcontrib>Shcherbakova, Polina V.</creatorcontrib><creatorcontrib>Gala, Manish K.</creatorcontrib><title>Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors</title><title>Clinical and translational gastroenterology</title><addtitle>Clin Transl Gastroenterol</addtitle><description>Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC).
We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations.
Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations.
Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - genetics</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA2 Protein - genetics</subject><subject>Clinical Decision-Making - methods</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Datasets as Topic</subject><subject>DNA Mismatch Repair - drug effects</subject><subject>DNA Mismatch Repair - genetics</subject><subject>DNA Mutational Analysis - methods</subject><subject>DNA Polymerase II - genetics</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - drug therapy</subject><subject>Endometrial Neoplasms - genetics</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Exome Sequencing</subject><subject>Female</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Male</subject><subject>Metadata</subject><subject>Metastasis</subject><subject>Microsatellite Instability</subject><subject>Microsatellite Repeats - genetics</subject><subject>Mutation</subject><subject>Poly-ADP-Ribose Binding Proteins - genetics</subject><subject>Precision medicine</subject><subject>Recombinational DNA Repair - drug effects</subject><subject>Recombinational DNA Repair - genetics</subject><subject>Tumors</subject><issn>2155-384X</issn><issn>2155-384X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkV1rFDEUhoNYbKn9CcqAN95Mm6-ZTG4EWVq3ULG0K3gXMpmzu6mZZE0yloI_3nS3lrUJ4eQkz3k5Hwi9I_iUcIblmcmrU7y_CJev0BElTVOzjv94vXc_RCcp3T1CHNNOyjfokFHWUEH5EfozD2NwYRWmVN2ACWNvvc42-OJttI3VIk7ebF9SdR1hsCZX84cNxHHKO9D66qs1MSSdwTmbobrNundQzYpwBJO1q7QfqnM_hBFytMVfTGOI6S06WGqX4OTJHqPvF-eL2by--vblcvb5qja846TuQPB-4AYwLulLTMDIHgjTS62l7EVDacuNaakUPaXlpTWybNwKLAAPgh2jTzvdzdSPMBjwOWqnNtGOOj6ooK36_8fbtVqF30oQ3mDWFoGPTwIx_JogZTXaZEq12kPpnKJMirbDlLCCfniB3oUp-lKeoryRnHZkSzU76rFvKcLyORmC1XbEqoxYvRxxiXu_X8lz1L-BFoDvgPvgMsT00033ENUatMtrhYmgGEteU1wsK6J1OSXtv-XItKU</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Lee, Minyi</creator><creator>Eng, George</creator><creator>Barbari, Stephanie R.</creator><creator>Deshpande, Vikram</creator><creator>Shcherbakova, Polina V.</creator><creator>Gala, Manish K.</creator><general>Wolters Kluwer</general><general>Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200301</creationdate><title>Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors</title><author>Lee, Minyi ; Eng, George ; Barbari, Stephanie R. ; Deshpande, Vikram ; Shcherbakova, Polina V. ; Gala, Manish K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4841-8e74bd4ce00899901ec9be13afaa99b752264cc6297b2299b6c9c9c06707e0d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - genetics</topic><topic>BRCA1 Protein - genetics</topic><topic>BRCA2 Protein - genetics</topic><topic>Clinical Decision-Making - methods</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Datasets as Topic</topic><topic>DNA Mismatch Repair - drug effects</topic><topic>DNA Mismatch Repair - genetics</topic><topic>DNA Mutational Analysis - methods</topic><topic>DNA Polymerase II - genetics</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - drug therapy</topic><topic>Endometrial Neoplasms - genetics</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Exome Sequencing</topic><topic>Female</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Male</topic><topic>Metadata</topic><topic>Metastasis</topic><topic>Microsatellite Instability</topic><topic>Microsatellite Repeats - genetics</topic><topic>Mutation</topic><topic>Poly-ADP-Ribose Binding Proteins - genetics</topic><topic>Precision medicine</topic><topic>Recombinational DNA Repair - drug effects</topic><topic>Recombinational DNA Repair - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Minyi</creatorcontrib><creatorcontrib>Eng, George</creatorcontrib><creatorcontrib>Barbari, Stephanie R.</creatorcontrib><creatorcontrib>Deshpande, Vikram</creatorcontrib><creatorcontrib>Shcherbakova, Polina V.</creatorcontrib><creatorcontrib>Gala, Manish K.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical and translational gastroenterology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Minyi</au><au>Eng, George</au><au>Barbari, Stephanie R.</au><au>Deshpande, Vikram</au><au>Shcherbakova, Polina V.</au><au>Gala, Manish K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors</atitle><jtitle>Clinical and translational gastroenterology</jtitle><addtitle>Clin Transl Gastroenterol</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>11</volume><issue>3</issue><spage>e00149</spage><epage>e00149</epage><pages>e00149-e00149</pages><issn>2155-384X</issn><eissn>2155-384X</eissn><abstract>Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC).
We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations.
Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations.
Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.</abstract><cop>United States</cop><pub>Wolters Kluwer</pub><pmid>32352724</pmid><doi>10.14309/ctg.0000000000000149</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics BRCA1 Protein - genetics BRCA2 Protein - genetics Clinical Decision-Making - methods Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Datasets as Topic DNA Mismatch Repair - drug effects DNA Mismatch Repair - genetics DNA Mutational Analysis - methods DNA Polymerase II - genetics Drug Resistance, Neoplasm - genetics Endometrial cancer Endometrial Neoplasms - drug therapy Endometrial Neoplasms - genetics Endometrial Neoplasms - pathology Exome Sequencing Female Genomes Genomics Humans Immunotherapy Male Metadata Metastasis Microsatellite Instability Microsatellite Repeats - genetics Mutation Poly-ADP-Ribose Binding Proteins - genetics Precision medicine Recombinational DNA Repair - drug effects Recombinational DNA Repair - genetics Tumors |
| title | Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors |
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