Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer
Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses�...
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| Veröffentlicht in: | JNCI : Journal of the National Cancer Institute 2018-12, Vol.110 (12), p.1409-1417 |
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| creator | Loree, Jonathan M Bailey, Ann M Johnson, Amber M Yu, Yao Wu, Wenhui Bristow, Christopher A Davis, Jennifer S Shaw, Kenna R Broaddus, Russell Banks, Kimberly C Lanman, Richard B Meric-Bernstam, Funda Overman, Michael J Kopetz, Scott Raghav, Kanwal |
| description | Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC.
We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.
ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival.
MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3. |
| doi_str_mv | 10.1093/jnci/djy067 |
| format | Article |
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We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.
ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival.
MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.</description><identifier>ISSN: 0027-8874</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djy067</identifier><identifier>PMID: 29718453</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Aged ; Biomarkers, Tumor ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; Exons ; Female ; Follow-Up Studies ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Mutation ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-3 - genetics ; Retrospective Studies</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2018-12, Vol.110 (12), p.1409-1417</ispartof><rights>The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c344t-98a1df2425d85b1425daf3860bd4fd3f7852519725b2032c7c90df74c9579f9d3</citedby><cites>FETCH-LOGICAL-c344t-98a1df2425d85b1425daf3860bd4fd3f7852519725b2032c7c90df74c9579f9d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29718453$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Loree, Jonathan M</creatorcontrib><creatorcontrib>Bailey, Ann M</creatorcontrib><creatorcontrib>Johnson, Amber M</creatorcontrib><creatorcontrib>Yu, Yao</creatorcontrib><creatorcontrib>Wu, Wenhui</creatorcontrib><creatorcontrib>Bristow, Christopher A</creatorcontrib><creatorcontrib>Davis, Jennifer S</creatorcontrib><creatorcontrib>Shaw, Kenna R</creatorcontrib><creatorcontrib>Broaddus, Russell</creatorcontrib><creatorcontrib>Banks, Kimberly C</creatorcontrib><creatorcontrib>Lanman, Richard B</creatorcontrib><creatorcontrib>Meric-Bernstam, Funda</creatorcontrib><creatorcontrib>Overman, Michael J</creatorcontrib><creatorcontrib>Kopetz, Scott</creatorcontrib><creatorcontrib>Raghav, Kanwal</creatorcontrib><title>Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC.
We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.
ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival.
MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.</description><subject>Aged</subject><subject>Biomarkers, Tumor</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Exons</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene Frequency</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Staging</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-3 - genetics</subject><subject>Retrospective Studies</subject><issn>0027-8874</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkEtLw0AUhQdRbH2s3EuWgsTOK5kMiGBDfUCLILoeJvPQlGmmziRC_70JrUXv4p7FPZxz-QC4QPAGQU4my0bVE73cwJwdgDGiOUwxgtkhGEOIWVoUjI7ASYxL2A_H9BiMMGeooBkZg9uFd0Z1ToZkLhsdlVybxNtk9jqd4smwSbLoWtkanZTe-WBUK11SykaZcAaOrHTRnO_0FLw_zN7Kp3T-8vhc3s9TRShtU15IpC2mONNFVqFBpSVFDitNrSaWFRnOEGc4qzAkWDHFobaMKp4xbrkmp-Bum7vuqpXRyjRtkE6sQ72SYSO8rMX_S1N_ig__LXLMMeOoD7jaBQT_1ZnYilUdlXFONsZ3UfS1hPSgOOyt11urCj7GYOy-BkEx8BYDb7Hl3bsv_3629_4CJj_HCXuP</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Loree, Jonathan M</creator><creator>Bailey, Ann M</creator><creator>Johnson, Amber M</creator><creator>Yu, Yao</creator><creator>Wu, Wenhui</creator><creator>Bristow, Christopher A</creator><creator>Davis, Jennifer S</creator><creator>Shaw, Kenna R</creator><creator>Broaddus, Russell</creator><creator>Banks, Kimberly C</creator><creator>Lanman, Richard B</creator><creator>Meric-Bernstam, Funda</creator><creator>Overman, Michael J</creator><creator>Kopetz, Scott</creator><creator>Raghav, Kanwal</creator><general>Oxford University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20181201</creationdate><title>Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer</title><author>Loree, Jonathan M ; Bailey, Ann M ; Johnson, Amber M ; Yu, Yao ; Wu, Wenhui ; Bristow, Christopher A ; Davis, Jennifer S ; Shaw, Kenna R ; Broaddus, Russell ; Banks, Kimberly C ; Lanman, Richard B ; Meric-Bernstam, Funda ; Overman, Michael J ; Kopetz, Scott ; Raghav, Kanwal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c344t-98a1df2425d85b1425daf3860bd4fd3f7852519725b2032c7c90df74c9579f9d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Aged</topic><topic>Biomarkers, Tumor</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Exons</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene Frequency</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Staging</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-3 - genetics</topic><topic>Retrospective Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Loree, Jonathan M</creatorcontrib><creatorcontrib>Bailey, Ann M</creatorcontrib><creatorcontrib>Johnson, Amber M</creatorcontrib><creatorcontrib>Yu, Yao</creatorcontrib><creatorcontrib>Wu, Wenhui</creatorcontrib><creatorcontrib>Bristow, Christopher A</creatorcontrib><creatorcontrib>Davis, Jennifer S</creatorcontrib><creatorcontrib>Shaw, Kenna R</creatorcontrib><creatorcontrib>Broaddus, Russell</creatorcontrib><creatorcontrib>Banks, Kimberly C</creatorcontrib><creatorcontrib>Lanman, Richard B</creatorcontrib><creatorcontrib>Meric-Bernstam, Funda</creatorcontrib><creatorcontrib>Overman, Michael J</creatorcontrib><creatorcontrib>Kopetz, Scott</creatorcontrib><creatorcontrib>Raghav, Kanwal</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Loree, Jonathan M</au><au>Bailey, Ann M</au><au>Johnson, Amber M</au><au>Yu, Yao</au><au>Wu, Wenhui</au><au>Bristow, Christopher A</au><au>Davis, Jennifer S</au><au>Shaw, Kenna R</au><au>Broaddus, Russell</au><au>Banks, Kimberly C</au><au>Lanman, Richard B</au><au>Meric-Bernstam, Funda</au><au>Overman, Michael J</au><au>Kopetz, Scott</au><au>Raghav, Kanwal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>J Natl Cancer Inst</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>110</volume><issue>12</issue><spage>1409</spage><epage>1417</epage><pages>1409-1417</pages><issn>0027-8874</issn><eissn>1460-2105</eissn><abstract>Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC.
We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.
ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival.
MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>29718453</pmid><doi>10.1093/jnci/djy067</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Biomarkers, Tumor Colorectal Neoplasms - genetics Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Exons Female Follow-Up Studies Gene Frequency Genetic Association Studies Genetic Predisposition to Disease Humans Male Middle Aged Mutation Neoplasm Grading Neoplasm Staging Prognosis Proportional Hazards Models Receptor, ErbB-2 - genetics Receptor, ErbB-3 - genetics Retrospective Studies |
| title | Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer |
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