Dataset Information

Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis.

ABSTRACT: Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined.To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM.This retrospective single-center study was conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13.Resection of CRLM.Overall survival (OS) and recurrence-free survival.A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P?=?.82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P?=?.02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95% CI, 1.05-2.27; P?=?.03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95% CI, 0.83-2.62; P?=?.19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95% CI, 1.00-3.17; P?=?.05) and G12S (HR, 3.33; 95% CI, 1.22-9.10; P?=?.02) were associated with worse OS compared with patients with wtKRAS (both P?

SUBMITTER: Margonis GA

PROVIDER: S-EPMC4696064 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis.

Margonis Georgios Antonios GA Kim Yuhree Y Spolverato Gaya G Ejaz Aslam A Gupta Rohan R Cosgrove David D Anders Robert R Karagkounis Georgios G Choti Michael A MA Pawlik Timothy M TM

JAMA surgery 20150801 8

<h4>Importance</h4>Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined.<h4>Objective</h4>To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM.<h4>Design, setting, and participants</h4>This retrospective sin ...[more]

PMID: 26038887

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Project description:BackgroundApproximately 40% of colorectal cancer (CRC) cases are linked to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. KRAS mutations are associated with poor CRC prognosis, especially KRAS codon 12 mutation, which is associated with metastasis and poorer survival. However, the clinicopathological characteristics and prognosis of KRAS codon 13 mutation in CRC remain unclear.AimTo evaluate the clinicopathological characteristics and prognostic value of codon-specific KRAS mutations, especially in codon 13.MethodsThis retrospective, single-center, observational cohort study included patients who underwent surgery for stage I-III CRC between January 2009 and December 2019. Patients with KRAS mutation status confirmed by molecular pathology reports were included. The relationships between clinicopathological characteristics and individual codon-specific KRAS mutations were analyzed. Survival data were analyzed to identify codon-specific KRAS mutations as recurrence-related factors using the Cox proportional hazards regression model.ResultsAmong the 2203 patients, the incidence of KRAS codons 12, 13, and 61 mutations was 27.7%, 9.1%, and 1.3%, respectively. Both KARS codons 12 and 13 mutations showed a tendency to be associated with clinical characteristics, but only codon 12 was associated with pathological features, such as stage of primary tumor (T stage), lymph node involvement (N stage), vascular invasion, perineural invasion, tumor size, and microsatellite instability. KRAS codon 13 mutation showed no associations (77.2% vs 85.3%, P = 0.159), whereas codon 12 was associated with a lower 5-year recurrence-free survival rate (78.9% vs 75.5%, P = 0.025). In multivariable analysis, along with T and N stages and vascular and perineural invasion, only codon 12 (hazard ratio: 1.399; 95% confidence interval: 1.034-1.894; P = 0.030) among KRAS mutations was an independent risk factor for recurrence.ConclusionThis study provides evidence that KRAS codon 13 mutation is less likely to serve as a prognostic biomarker than codon 12 mutation for CRC in a large-scale cohort.

Project description:BackgroundMutations in KRAS, BRAF and PIK3CA are the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis.MethodsThe sequences of exon 2 of KRAS, exon 15 of BRAF and exons 9 and 20 of PIK3CA were evaluated by PCR and direct sequencing using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues from primary CRC tumors of 214 patients (colon/rectum: 126/88).ResultsKRAS, BRAF and PIK3CA mutations were identified in 44.9% (96/214), 4.2% (9/214) and 12.3% (26/212) CRCs, respectively. The most frequent mutations in KRAS, BRAF and PIK3CA were G12D, V600E and H1047R, respectively. All BRAF and 80.8% PIK3CA mutations were from colon cancer patients. BRAF V600E was associated with advanced TNM (P < 0.001), more distant metastases (P = 0.025), and worse overall survival (OS, P < 0.001; multivariate HR = 4.2, P = 0.004) in colon cancer patients. Compared with KRAS wt/BRAF wt CRC patients (N = 109), those with KRAS codon 13 mutations (N = 25) had significantly worse OS (P = 0.016; multivariate HR = 2.7, P = 0.011), whereas KRAS codon 12-mutated cases were not significantly associated with survival. Among the three most common KRAS mutations, G13D (N = 23) showed significant association with poor OS (P = 0.024; multivariate HR = 2.6, P = 0.016) compared with KRAS wt/BRAF wt patients.ConclusionOur findings indicate that PI3K/RAS-RAF signaling pathway genes are frequently mutated in Chinese CRC patients, but have different characteristics than found in Western patients. BRAF V600E is an independent prognostic factor for Chinese patients. Our finding that KRAS codon 13 mutations (in particular G13D) are associated with inferior survival in BRAF wild-type CRCs in Chinese patients was not reported thus far. Our data emphasizes the importance of prospective evaluation of molecular features in CRC patients, because a single mutation type may represent a distinct biologic effect and clinical implication.

Dataset Information

Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis.

Publications

Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis.

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