BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer
Somatic mutation status at , and is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters. We profiled 2,157 aCRCs for somatic mutations i...
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| Veröffentlicht in: | Clinical cancer research 2017-06, Vol.23 (11), p.2742-2749 |
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| creator | Summers, Matthew G Smith, Christopher G Maughan, Timothy S Kaplan, Richard Escott-Price, Valentina Cheadle, Jeremy P |
| description | Somatic mutation status at
, and
is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.
We profiled 2,157 aCRCs for somatic mutations in
, and
and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.
mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61;
= 6.4 × 10
and HR, 1.53; 95% CI, 1.26-1.86;
= 1.5 × 10
, respectively]. For
more c.1781A>G (p.D594G) CRCs carried
mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178),
= 9.0 × 10
]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28;
= 1.0 × 10
), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31;
= 0.37); this intralocus difference was significant (
= 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15),
= 3.7 × 10
]. For
, 5% (3/60) of codon 61 mutant colorectal cancers had
mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (
= 7.9 × 10
). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99;
= 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58;
= 0.48).
Our data show considerable intralocus variation in the outcomes of mutations in
and
These data need to be considered in patient management and personalized cancer therapy.
. |
| doi_str_mv | 10.1158/1078-0432.ccr-16-1541 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1911619226</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1983417833</sourcerecordid><originalsourceid>FETCH-LOGICAL-c483t-27c39b56e8222842a3c38f85c34357ce8e9cbfe0361f815f8da38198f76274523</originalsourceid><addsrcrecordid>eNqFkctrGzEQh0VpaF79E1oEvfSyyY7ee3S2zQNMAnbSY4Usj2DDeuVKu4b895XJ45BLLhoNfPNjho-Qb1CfAUhzDrU2VS04O_M-VaAqkAI-kSOQUlecKfm5_F-ZQ3Kc82Ndg4BafCGHTBuQXOoj8vdiMbukbljT28VsSefRT7labtF3ofP0j0udG8ZMr90O6a8uBEw4jPRuGn3cYKZxoMsp7bqd6-kYaRv7mNCPpWvd4DGdkoPg-oxfX-oJebj8fd9eV_O7q5t2Nq-8MHysmPa8WUmFhjFmBHPccxOM9FyULT0abPwqYM0VhLJ5MGvHDTQmaMW0kIyfkJ_PudsU_02YR7vpsse-dwPGKVtoABQ0jKmPUcOV5qq8Bf3xDn2MUxrKISXQcAHacF4o-Uz5FHNOGOw2dRuXnizUdu_K7j3YvQfbtgsLyu5dlbnvL-nTaoPrt6lXOfw_sIuMlQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1983417833</pqid></control><display><type>article</type><title>BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Summers, Matthew G ; Smith, Christopher G ; Maughan, Timothy S ; Kaplan, Richard ; Escott-Price, Valentina ; Cheadle, Jeremy P</creator><creatorcontrib>Summers, Matthew G ; Smith, Christopher G ; Maughan, Timothy S ; Kaplan, Richard ; Escott-Price, Valentina ; Cheadle, Jeremy P</creatorcontrib><description>Somatic mutation status at
, and
is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.
We profiled 2,157 aCRCs for somatic mutations in
, and
and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.
mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61;
= 6.4 × 10
and HR, 1.53; 95% CI, 1.26-1.86;
= 1.5 × 10
, respectively]. For
more c.1781A>G (p.D594G) CRCs carried
mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178),
= 9.0 × 10
]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28;
= 1.0 × 10
), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31;
= 0.37); this intralocus difference was significant (
= 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15),
= 3.7 × 10
]. For
, 5% (3/60) of codon 61 mutant colorectal cancers had
mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (
= 7.9 × 10
). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99;
= 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58;
= 0.48).
Our data show considerable intralocus variation in the outcomes of mutations in
and
These data need to be considered in patient management and personalized cancer therapy.
.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.ccr-16-1541</identifier><identifier>PMID: 27815357</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Aged ; Cancer ; Codons ; Colon ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Colorectal Neoplasms - therapy ; Confidence intervals ; Design parameters ; Experimental design ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; GTP Phosphohydrolases - genetics ; Humans ; K-Ras protein ; Male ; Medical prognosis ; Membrane Proteins - genetics ; Microsatellite Instability ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide - genetics ; Precision Medicine ; Prognosis ; Proportional Hazards Models ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins p21(ras) - genetics ; Stability ; Survival</subject><ispartof>Clinical cancer research, 2017-06, Vol.23 (11), p.2742-2749</ispartof><rights>2016 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Jun 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-27c39b56e8222842a3c38f85c34357ce8e9cbfe0361f815f8da38198f76274523</citedby><cites>FETCH-LOGICAL-c483t-27c39b56e8222842a3c38f85c34357ce8e9cbfe0361f815f8da38198f76274523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27815357$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Summers, Matthew G</creatorcontrib><creatorcontrib>Smith, Christopher G</creatorcontrib><creatorcontrib>Maughan, Timothy S</creatorcontrib><creatorcontrib>Kaplan, Richard</creatorcontrib><creatorcontrib>Escott-Price, Valentina</creatorcontrib><creatorcontrib>Cheadle, Jeremy P</creatorcontrib><title>BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Somatic mutation status at
, and
is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.
We profiled 2,157 aCRCs for somatic mutations in
, and
and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.
mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61;
= 6.4 × 10
and HR, 1.53; 95% CI, 1.26-1.86;
= 1.5 × 10
, respectively]. For
more c.1781A>G (p.D594G) CRCs carried
mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178),
= 9.0 × 10
]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28;
= 1.0 × 10
), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31;
= 0.37); this intralocus difference was significant (
= 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15),
= 3.7 × 10
]. For
, 5% (3/60) of codon 61 mutant colorectal cancers had
mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (
= 7.9 × 10
). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99;
= 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58;
= 0.48).
Our data show considerable intralocus variation in the outcomes of mutations in
and
These data need to be considered in patient management and personalized cancer therapy.
.</description><subject>Aged</subject><subject>Cancer</subject><subject>Codons</subject><subject>Colon</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Colorectal Neoplasms - therapy</subject><subject>Confidence intervals</subject><subject>Design parameters</subject><subject>Experimental design</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>GTP Phosphohydrolases - genetics</subject><subject>Humans</subject><subject>K-Ras protein</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Membrane Proteins - genetics</subject><subject>Microsatellite Instability</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Precision Medicine</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Stability</subject><subject>Survival</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctrGzEQh0VpaF79E1oEvfSyyY7ee3S2zQNMAnbSY4Usj2DDeuVKu4b895XJ45BLLhoNfPNjho-Qb1CfAUhzDrU2VS04O_M-VaAqkAI-kSOQUlecKfm5_F-ZQ3Kc82Ndg4BafCGHTBuQXOoj8vdiMbukbljT28VsSefRT7labtF3ofP0j0udG8ZMr90O6a8uBEw4jPRuGn3cYKZxoMsp7bqd6-kYaRv7mNCPpWvd4DGdkoPg-oxfX-oJebj8fd9eV_O7q5t2Nq-8MHysmPa8WUmFhjFmBHPccxOM9FyULT0abPwqYM0VhLJ5MGvHDTQmaMW0kIyfkJ_PudsU_02YR7vpsse-dwPGKVtoABQ0jKmPUcOV5qq8Bf3xDn2MUxrKISXQcAHacF4o-Uz5FHNOGOw2dRuXnizUdu_K7j3YvQfbtgsLyu5dlbnvL-nTaoPrt6lXOfw_sIuMlQ</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Summers, Matthew G</creator><creator>Smith, Christopher G</creator><creator>Maughan, Timothy S</creator><creator>Kaplan, Richard</creator><creator>Escott-Price, Valentina</creator><creator>Cheadle, Jeremy P</creator><general>American Association for Cancer Research Inc</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>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20170601</creationdate><title>BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer</title><author>Summers, Matthew G ; Smith, Christopher G ; Maughan, Timothy S ; Kaplan, Richard ; Escott-Price, Valentina ; Cheadle, Jeremy P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-27c39b56e8222842a3c38f85c34357ce8e9cbfe0361f815f8da38198f76274523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aged</topic><topic>Cancer</topic><topic>Codons</topic><topic>Colon</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Colorectal Neoplasms - therapy</topic><topic>Confidence intervals</topic><topic>Design parameters</topic><topic>Experimental design</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>GTP Phosphohydrolases - genetics</topic><topic>Humans</topic><topic>K-Ras protein</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Membrane Proteins - genetics</topic><topic>Microsatellite Instability</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Precision Medicine</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Stability</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Summers, Matthew G</creatorcontrib><creatorcontrib>Smith, Christopher G</creatorcontrib><creatorcontrib>Maughan, Timothy S</creatorcontrib><creatorcontrib>Kaplan, Richard</creatorcontrib><creatorcontrib>Escott-Price, Valentina</creatorcontrib><creatorcontrib>Cheadle, Jeremy P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Summers, Matthew G</au><au>Smith, Christopher G</au><au>Maughan, Timothy S</au><au>Kaplan, Richard</au><au>Escott-Price, Valentina</au><au>Cheadle, Jeremy P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>23</volume><issue>11</issue><spage>2742</spage><epage>2749</epage><pages>2742-2749</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Somatic mutation status at
, and
is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.
We profiled 2,157 aCRCs for somatic mutations in
, and
and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.
mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61;
= 6.4 × 10
and HR, 1.53; 95% CI, 1.26-1.86;
= 1.5 × 10
, respectively]. For
more c.1781A>G (p.D594G) CRCs carried
mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178),
= 9.0 × 10
]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28;
= 1.0 × 10
), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31;
= 0.37); this intralocus difference was significant (
= 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15),
= 3.7 × 10
]. For
, 5% (3/60) of codon 61 mutant colorectal cancers had
mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (
= 7.9 × 10
). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99;
= 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58;
= 0.48).
Our data show considerable intralocus variation in the outcomes of mutations in
and
These data need to be considered in patient management and personalized cancer therapy.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>27815357</pmid><doi>10.1158/1078-0432.ccr-16-1541</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical cancer research, 2017-06, Vol.23 (11), p.2742-2749 |
| issn | 1078-0432 1557-3265 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Aged Cancer Codons Colon Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Colorectal Neoplasms - therapy Confidence intervals Design parameters Experimental design Female Genetic Association Studies Genetic Predisposition to Disease GTP Phosphohydrolases - genetics Humans K-Ras protein Male Medical prognosis Membrane Proteins - genetics Microsatellite Instability Middle Aged Mutation Polymorphism, Single Nucleotide - genetics Precision Medicine Prognosis Proportional Hazards Models Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics Stability Survival |
| title | BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer |
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