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 fi Asp; G12D, Gly fi Asp, G13D; Gly fi 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 5 0.038). With MSI, specific KRAS and BRAF V600E mutations, 3 distinct prognostic subgroups were observed in univariate (p 5 0.006) and multivariable (p 5 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.Sporadic colorectal cancer (CRC) is a heterogeneous disease arising from at least 2 different and seemingly independent pathways, namely the chromosomal instability (CIN, or microsatellite stable, MSS) and microsatellite instability (MSI) pathways. 1 CRCs from the MSS pathway are thought to originate from a relatively uniform and linear accumulation of genetic changes in APC, KRAS and TP53. 2 However, in practice, only 10% of these tumors are characterized by this classic genotype. 3,4 Sporadic MSI-high (MSI-H) cancers occur through promoter hypermethylation of the MLH1 gene, more frequently found in females, and tend to be poorly differentiated tumors, of mucinous subtype, associated with a Crohn's like reaction at the invasive tumor front and often harboring somatic mutations in BRAF V600E . 5-7 MSI-H CRCs can also arise in the context of Lynch syndrome/hereditary nonpolyposis CRC (HNPCC), an autosomal dominant disorder, accounting for 3% of all CRC cases, characterized by germline mutations of mismatch-repair genes. 8 Both sporadic and Lynch syndrome-associated MSI-H tumors are characterized by dense tumor-infiltrating lymphocyte populations and less frequent metastases suggesting enhanced immunogenicity irrespective of the mechanism of DNA mismatch repair inactivation. 9,10 Recently, MSI status, BRAF V600E and KRAS mutation status have attracted significant attention due to their potential prognostic and predictive role in CRC. 11 On one hand, patients with MSI-H cancers are specifically thought to have a favorable outcome; yet on the other hand, they are generally nonresponsive to certain chemotherapeutic agents such as 5-flurouracil (5-FU). 6,12 The prognostic effect of somatic KRAS mutations, described in 30...

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 adepartment 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.