Colorectal Cancer With Mutation in <i>BRAF</i>, <i>KRAS</i>, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation

Nagasaka, Takeshi; Sasamoto, Hiromi; Notohara, Kenji; Cullings, Harry M.; Takeda, Masanori; Kimura, Keigo; Kambara, Takeshi; MacPhee, Donald G.; Young, Joanne; Leggett, Barbara A.; Jass, Jeremy R.; Tanaka, Noriaki; Matsubara, Nagahide

doi:10.1200/jco.2004.02.154

Cited by 207 publications

(215 citation statements)

References 16 publications

Supporting

Mentioning

196

Contrasting

Unclassified

Order By: Relevance

“…KRAS mutation, as well as low/indeterminate levels of MSI and CIMP, has been associated with methylation of MGMT by several authors. 21,22,42,43 In our study, we found that some KRAS-mutated carcinomas were associated with MGMT immunohistochemical loss of expression (borderline significance), MGMT methylation, and MSI-low/indeterminate phenotype. Of note, we found poor correlation between MGMT immunohistochemical loss of expression and MGMT methylation, as reported by others in colorectal carcinoma and glioblastoma.…”

Section: Discussionmentioning

confidence: 53%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

View full text Add to dashboard Cite

KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O 6 -methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wildtype carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; Po0.001), demonstrated mucinous differentiation (46 vs 31%; P ¼ 0.001) and were associated with different MSI status (Po0.001) and with MGMT methylation (47 vs 21%; P ¼ 0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P ¼ 0.001), mucinous differentiation (46 vs 25%; Po0.001), presence of a contiguous polyp (38 vs 22%; Po0.001), MGMT methylation (47 vs 26%; P ¼ 0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P ¼ 0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P ¼ 0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

show abstract

Section: Discussionmentioning

confidence: 53%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The concomitant existence of BRAF mutations or MLH1 promoter hypermethylation in LS patients has been extensively documented. 10,11,13,16,[18][19][20][21][26][27][28] The clinical usefulness of MLH1 hypermethylation analysis relies, in part, on the low prevalence observed. MLH1 hypermethylation analysis does not only outperform BRAF mutation analysis but it is also more cost-effective, in terms of incremental cost per additional MLH1 mutation carrier detected.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] However, the identification of hypermethylation in a limited number of LS tumors has made its use controversial. 10,[26][27][28] Issues that affect screening include the accuracy, sensitivity, and specificity of the test, the benefit to the patient, the possible negative ramifications of the results, and the cost. 8,[29][30][31] Before routine implementation in the clinical setting, it is critical to assess the analytical and clinical validity and the cost-effectiveness of BRAF mutation and MLH1 promoter hypermethylation.…”

Section: Introductionmentioning

confidence: 99%

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

View full text Add to dashboard Cite

The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

show abstract

“…The BRAF V600E mutation also increases NF-kB signaling (Ikenoue et al, 2003). This mutation is found in serrated polyps but not in adenomas (Kambara et al, 2004) and displays a striking correlation with MSI-H and CIMP (Nagasaka et al, 2004). KRAS mutations are found in a wider spectrum of early lesions, but never together with BRAF V600E, and are possibly caused by a defect in the MGMT repair gene (Esteller et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer

et al. 2007

View full text Add to dashboard Cite

Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation

Cited by 207 publications

References 16 publications

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer

Contact Info

Product

Resources

About