Intra-tumoral Heterogeneity of<i>KRAS</i>and<i>BRAF</i>Mutation Status in Patients with Advanced Colorectal Cancer (aCRC) and Cost-Effectiveness of Multiple Sample Testing

Richman, Susan D.; Chambers, Philip A.; Seymour, Matthew; Daly, Catherine; Grant, Sophie; Hemmings, Gemma; Quirke, Philip

doi:10.1155/2011/393521

Cited by 77 publications

(78 citation statements)

References 17 publications

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“…Of the 572 patients in the randomized population, 394 were tested for KRAS status with bidirectional sequencing and 453 were tested with the therascreen KRAS kit. Intratumoral heterogeneity with respect to KRAS mutation status has been previously reported 24,25 and may have contributed to the discordance between the analyses. In addition, several other factors may have contributed to the observed differences between the results from the therascreen KRAS kit and bidirectional sequencing, including differences in available tumor tissue samples between the analyses and the relative sensitivities of the assays.…”

Section: Commentmentioning

confidence: 84%

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Harbison

Horak

Ledeine

et al. 2013

Archives of Pathology & Laboratory Medicine

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Context.-The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.Objective.-To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy.Design.-Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes.Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P ¼ .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P ¼ .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing.Conclusions.-These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.

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Section: Commentmentioning

confidence: 84%

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Harbison

Horak

Ledeine

et al. 2013

Archives of Pathology & Laboratory Medicine

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“…By also taking into account intratumoural heterogeneity, 26 KRAS and BRAF mutations are well demonstrated mutually exclusive events in colorectal cancer. 27,28 Therefore, their coexistence, although very likely in different cellular subclones, might represent a peculiar feature of MUTYHassociated-polyposis carcinogenesis.…”

Section: M1mentioning

confidence: 99%

Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes

et al. 2013

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MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/ attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYHassociated-polyposis adenomas exhibited only c.34G4T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (Po0.001). Mutated MUTYH-associated-polyposis carcinomas showed KRAS c.34G4T transversions, prevalently occurring with BRAFV600E; none of the classical/ attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P ¼ 0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P ¼ 0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation.

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“…One report, analyzing 233 genes, indicated that there may be differences in as few as 3% of genes between primary and metastatic sites (10 (11,12). Although the number of cases surveyed was small, the frequency of acquired mutations identified was not negligible.…”

Section: Introductionmentioning

confidence: 99%

Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis

et al. 2011

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Abstract. Mutations at codons 12 and 13 of the KRAS gene have been identified as level I predictive biomarkers against the treatment of advanced colorectal cancer with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. It is thought that the genetic analysis of KRAS mutations associated with metastatic colorectal cancer can be routinely conducted using DNA obtained on one occasion from one organ, from the primary or a metastatic site, whichever is preferentially available. However, the issue of tumor heterogeneity resulting from acquired/intratumoral mutations remains. Recently, the possibility of acquired/intratumoral mutations in the KRAS gene has been reported by two research groups and has ranged from 7.4 to 15.4%. Specimens were collected from advanced colorectal cancer patients with resected primary, and at least one metastatic, site. Direct sequence analysis was performed for KRAS, BRAF and PIK3CA, and immunohistochemistry for glutathione S-transferase II (GSTP) and EGFR. In the current study, we identified an acquired mutation rate of approximately 11.1% in the KRAS gene (1/9). This figure is not negligible. Our observation indicates, particularly in the case of metastatic recurrence after a long interval, that there may be considerable tumor heterogeneity resulting from acquired or intratumoral mutations of the KRAS gene.

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Intra-tumoral Heterogeneity ofKRASandBRAFMutation Status in Patients with Advanced Colorectal Cancer (aCRC) and Cost-Effectiveness of Multiple Sample Testing

Cited by 77 publications

References 17 publications

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes

Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis

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