A CETP polymorphism improves the diagnostic power of clinical examination in patients with cardiovascular disease.

AIMS: Atherosclerosis is common and myocardial infarction, stroke and peripheral arterial occlusive disease are its devastating complications. Accurate risk prediction is urgently needed. We applied molecular tests to improve early clinical identification of patients threatened by a future course of complicated active atherosclerosis. METHODS AND RESULTS: Participants were men and women seeking care in a department of general internal medicine at an academic teaching hospital in Basel, Switzerland, between September 2003 and March 2005. A maximum number of 57 patients with a medical history of proven cardiovascular events and 57 age- and gender-matched patients without cardiovascular events were selected from this cohort of 269 individuals. One of nine common single nucleotide polymorphisms (SNPs) reportedly linked to cardiovascular disease was significantly associated with cardiovascular events (p = 0.02). For CETPrs708272, the allele number per patient predisposing to cardiovascular events improved the discriminating power of clinical phenotyping for active versus inactive atherosclerosis. The area under the curve of receiver operating characteristic (ROC) for clinical examination alone was 0.627 (95% CI 0.525-0.730, p = 0.02) and increased to 0.672 (95% CI 0.571-0.772, p = 0.002) when the polymorphism was included in the assessment. CONCLUSIONS: Information about common SNPs with high impact on the individual cardiovascular risk, such as CETPrs708272, may help to predict an active, symptomatic course atherosclerosis.

Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer.

Confounding effects of specific KRAS gene alterations on colorectal cancer (CRC) prognosis stratified by microsatellite instability (MSI) and BRAF(V600E) have not yet been investigated. The aim of our study was to evaluate the combined effects of MSI, BRAF(V600E) and specific KRAS mutation (Gly → Asp; G12D, Gly → Asp, G13D; Gly → Val; G12V) on prognosis in 404 sporadic and 94 hereditary CRC patients. MSI status was determined according to the Bethesda guidelines. Mutational status of KRAS and BRAF(V600E) was assessed by direct DNA sequencing. In sporadic CRC, KRAS G12D mutations had a negative prognostic effect compared to G13D and wild-type cancers (p = 0.038). With MSI, specific KRAS and BRAF(V600E) mutations, 3 distinct prognostic subgroups were observed in univariate (p = 0.006) and multivariable (p = 0.051) analysis: patients with (i) KRAS mutation G12D, G12V or BRAF(V600E) mutation, (ii) KRAS/BRAF(V600E) wild-type or KRAS G13D mutations in MSS/MSI-L and (iii) MSI-H and KRAS G13D mutations. Moreover, none of the sporadic MSI-H or hereditary patients with KRAS G13 mutations had a fatal outcome. Specific KRAS mutation is an informative prognostic factor in both sporadic and hereditary CRC and applied in an algorithm with BRAF(V600E) and MSI may identify sporadic CRC patients with poor clinical outcome.