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dc.contributor.authorImamura, Yuen_US
dc.contributor.authorLochhead, Paulen_US
dc.contributor.authorYamauchi, Maien_US
dc.contributor.authorKuchiba, Ayaen_US
dc.contributor.authorQian, Zhi Rongen_US
dc.contributor.authorLiao, Xiaoyunen_US
dc.contributor.authorNishihara, Reikoen_US
dc.contributor.authorJung, Seungyounen_US
dc.contributor.authorWu, Kanaen_US
dc.contributor.authorNosho, Katsuhikoen_US
dc.contributor.authorWang, Yaoyu Een_US
dc.contributor.authorPeng, Shouyongen_US
dc.contributor.authorBass, Adam Jen_US
dc.contributor.authorHaigis, Kevin Men_US
dc.contributor.authorMeyerhardt, Jeffrey Aen_US
dc.contributor.authorChan, Andrew Ten_US
dc.contributor.authorFuchs, Charles Sen_US
dc.contributor.authorOgino, Shujien_US
dc.date.accessioned2014-07-07T17:02:34Z
dc.date.issued2014en_US
dc.identifier.citationImamura, Y., P. Lochhead, M. Yamauchi, A. Kuchiba, Z. R. Qian, X. Liao, R. Nishihara, et al. 2014. “Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.” Molecular Cancer 13 (1): 135. doi:10.1186/1476-4598-13-135. http://dx.doi.org/10.1186/1476-4598-13-135.en
dc.identifier.issn1476-4598en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12406627
dc.description.abstractBackground: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear. Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI. Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation]. Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.en
dc.language.isoen_USen
dc.publisherBioMed Centralen
dc.relation.isversionofdoi:10.1186/1476-4598-13-135en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051153/pdf/en
dash.licenseLAAen_US
dc.subjectClinical outcomeen
dc.subjectColon canceren
dc.subjectGenetic changeen
dc.subjecten
dc.titleAnalyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature reviewen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalMolecular Canceren
dash.depositing.authorYamauchi, Maien_US
dc.date.available2014-07-07T17:02:34Z
dc.identifier.doi10.1186/1476-4598-13-135*
dash.authorsorderedfalse
dash.contributor.affiliatedKuchiba, Aya
dash.contributor.affiliatedLiao, Xiaoyun
dash.contributor.affiliatedYamauchi, Mai
dash.contributor.affiliatedPeng, Shouyong
dash.contributor.affiliatedHaigis, Kevin
dash.contributor.affiliatedChan, Andrew
dash.contributor.affiliatedBass, Adam
dash.contributor.affiliatedFuchs, Charles
dash.contributor.affiliatedNakashima, Reiko
dash.contributor.affiliatedMeyerhardt, Jeffrey
dash.contributor.affiliatedOgino, Shuji
dash.contributor.affiliatedWu, Kana


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