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The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large populationbased sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatelliteunstable tumors. (Cancer Res 2005; 65(14): 6063-9)

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Mutational analysis of KRAS codons 12 and 13 is standard for patients with metastatic colorectal cancer since mutations in these codons predict lack of response to anti-EGFR therapies. However, even among patients whose tumors are wildtype for KRAS codons 12 and 13, only a subset respond to therapy. Since additional activating mutations downstream of EGFR may also play a role in treatment resistance, we sought to establish the frequency of these mutations. We evaluated 2121 colorectal tumors for mutations in codons 12 and 13 of the KRAS gene. A subset of these samples, comprised of 513 samples wildtype for KRAS codons 12 and 13, were tested for mutations in codons 61 and 146 of KRAS, codon 600 of BRAF, and codons 12, 13, and 61 of NRAS. Mutation status was determined by targeted pyrosequencing. Mutations in KRAS codon 12 or 13 were identified in 900/2121 (42.4%) samples. Of the 513 wildtype samples tested for additional mutations, 78 samples were mutant for BRAF, 19 for KRAS codon 61, 17 for KRAS codon 146, and 26 for NRAS. In total, 140/513 (27.3%) tumors wildtype for KRAS codons 12 and 13 harbored a mutation in another of the RAS pathway genes. While further study is needed to determine the full therapeutic implications of mutations in these codons, mutational testing of these codons may be useful for identifying a significant proportion of patients who may also be resistant to anti-EGFR therapies.

BackgroundAbout half of Americans 50 to 75 years old do not follow recommended colorectal cancer (CRC) screening guidelines, leaving 40 million individuals unscreened. A simple blood test would increase screening compliance, promoting early detection and better patient outcomes. The objective of this study is to demonstrate the performance of an improved sensitivity blood-based Septin 9 (SEPT9) methylated DNA test for colorectal cancer. Study variables include clinical stage, tumor location and histologic grade.MethodsPlasma samples were collected from 50 untreated CRC patients at 3 institutions; 94 control samples were collected at 4 US institutions; samples were collected from 300 colonoscopy patients at 1 US clinic prior to endoscopy. SEPT9 methylated DNA concentration was tested in analytical specimens, plasma of known CRC cases, healthy control subjects, and plasma collected from colonoscopy patients.ResultsThe improved SEPT9 methylated DNA test was more sensitive than previously described methods; the test had an overall sensitivity for CRC of 90% (95% CI, 77.4% to 96.3%) and specificity of 88% (95% CI, 79.6% to 93.7%), detecting CRC in patients of all stages. For early stage cancer (I and II) the test was 87% (95% CI, 71.1% to 95.1%) sensitive. The test identified CRC from all regions, including proximal colon (for example, the cecum) and had a 12% false-positive rate. In a small prospective study, the SEPT9 test detected 12% of adenomas with a false-positive rate of 3%.ConclusionsA sensitive blood-based CRC screening test using the SEPT9 biomarker specifically detects a majority of CRCs of all stages and colorectal locations. The test could be offered to individuals of average risk for CRC who are unwilling or unable to undergo colonscopy.

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This study suggests that smoking cigarettes statistically significantly contributes to MSI in colon tumors. We estimate that approximately 21% of MSI in colon tumors may be attributable to cigarette smoking.

An attenuated form of familial adenomatous polyposis coli, AAPC, causes relatively few colonic polyps, but still carries a significant risk of colon cancer. The mutant alleles responsible for this attenuated phenotype have been mapped in several families to the adenomatous polyposis coli (APC) locus on human chromosome 5q. Four distinct mutations in the APC gene have now been identified in seven AAPC families. These mutations that predict truncation products, either by single base pair changes or frameshifts, are similar to mutations identified in families with classical APC. However, they differ in that the four mutated sites are located very close to one another and nearer the 5' end of the APC gene than any base substitutions or small deletions yet discovered in patients with classical APC.