Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer

Nagasaka, Takeshi; Koi, Minoru; Kloor, Matthias; Gebert, Johannes; Vilkin, Alex; Nishida, Naoshi; Shin, Sung Kwan; Sasamoto, Hiromi; Tanaka, Noriaki; Matsubara, Nagahide; Boland, C. Richard; Goel, Ajay

doi:10.1053/j.gastro.2008.02.094

Cited by 116 publications

(127 citation statements)

References 34 publications

(15 reference statements)

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“…Although KRAS mutation has been extensively studied in colon cancer, its association with clinicopathologic features, survival or molecular features such as CpG island methylator phenotype status have yielded conflicting results. 42,50 In our series, KRAS mutation status was not associated with any clinicopathologic features or survival in signet ring cell carcinoma. KRAS and/or BRAF V600E mutations were seen in 79% of signet ring cell carcinomas.…”

Section: Discussionmentioning

confidence: 49%

“…[20][21][22][23] It has been argued that CpG island methylation phenotype-positive tumors constitute a distinct subtype of colorectal cancer, and have been variously associated with different features such as BRAF mutation, KRAS mutation, favorable prognosis and adverse outcome. [24][25][26][27][28][29][30]42 These differences are likely related to different criteria used for defining CpG island methylation phenotype-positive status, as well as the number and type of markers used. The role of methylation in signet ring cell carcinoma has not been systematically explored.…”

Section: Discussionmentioning

confidence: 99%

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Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with highlevel microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotypepositive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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“…32,33 Importantly, B60-80% of CIMP-H tumors harbor mutations in BRAF, and CIMP-H tumors rarely, if ever, demonstrate KRAS mutations. 31,34 In addition, CIMP-H colorectal carcinomas often demonstrate methylation of the p16 promoter, resulting in diminished or absent p16 protein expression. In our analysis, very few of the colorectal carcinomas demonstrated BRAF V600E mutations, indicating that the promoter methylation of CpG islands (CIMP-H) is not important in the neoplastic progression of colorectal carcinoma in young patients.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

et al. 2012

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Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (r40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients 440 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients r40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients 440 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (Po0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P ¼ 0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P ¼ 0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P ¼ 0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P ¼ 0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P ¼ 0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two

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“…Rather, tumor-suppressor genes are inactivated by widespread epigenetic silencing known as CpG Island Methylator Phenotype (CIMP) 2 often accompanied by the somatic BRAF p.V600E mutation. [3][4][5] CIMP colorectal cancers are associated with clinicopathological features such as proximal location, poor grade, presence of tumor-infiltrating lymphocytes, and mucinous differentiation, as well as frequently demonstrating molecular somatic events including the BRAF p.V600E mutation and high levels of microsatellite instability, but with much lower levels of TP53 mutation than their chromosomal unstable colorectal carcinoma counterparts. [6][7][8][9][10][11][12] Mucins are high-molecular weight proteins characterized by the presence of large amino acid tandem repeat sequences that show allelic size variation.…”

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confidence: 99%

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

et al. 2013

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Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (425% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all Po0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.

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Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer

Cited by 116 publications

References 34 publications

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

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