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Background & Aims-5-FU-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy.

Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.

BackgroundLynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population.MethodsUniversal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed.ResultsOne hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques.ConclusionThe prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.

Inactivation of MLH1 due to promoter hypermethylation strongly suggests a sporadic origin , providing exclusion criteria for Lynch syndrome. The aim of this study is to compare the utility of methylation analysis of MLH1 and BRAF V600E mutations for the selection of patients with MLH1 negative colorectal cancer for genetic testing. MLH1 methylation status was evaluated by MethyLight and methylation-specific MLPA (MS-MLPA) in tumor DNA from 73 colorectal cancer patients with loss of MLH1 protein expression. These tumors were analyzed for BRAF V600E mutations , and genetic testing for germline MLH1 mutations was performed in all corresponding patients. Ten patients had germline mutations in MLH1 and none of their tumors showed significant MLH1 methylation or BRAF V600E mutation. MLH1 genetic testing excluded patients by MethyLight in 47 patients (64%) , by MS-MLPA in 49 (67%) , and BRAF V600E mutation in only 25 patients (34%) ( 2 P ‫؍‬ 0.00001). Specificity was 75% for MethyLight , 78% for MS-MLPA and 40% for BRAF V600E mutation. The use of MethyLight or MS-MLPA instead of BRAF mutation resulted in a cost reduction of 41% and 45% , respectively , per every MLH1 mutation detected. Taken together , methylation analysis of MLH1 shows better performance characteristics than BRAF V600E mutation in the selection of patients for genetic testing of MLH1 , especially when using