How and when to search for microsatellite instability in colorectal cancer in 2008?

Hereditary non polyposis colorectal cancer or Lynch syndrome is due to germline mutation of one the DNA mismatch repair genes. This mutation is associated with an unstable phenotype in tumor DNA characterized by new microsatellite alleles that ore absent in matching normal DNA. Besides the Bethesda reference panel, a new panel of 5 mononucleotide microsatellites (BAT25, BAT26, NR21, NR24, NR27) has been proposed, which is more sensitive and faster to use in a multiplex PCR assay. In tumor cells, immunohistochemistry detects the loss of expression of either MLHI, MSH2, MSH6 or PMS2 protein, corresponding to the mutated gene. Immunohistochemistry guides germline analysis, except for MLHI extinction which may correspond to either MLHI germline mutation or methylation of MLH1 promoter resulting in inactivation. The latter is mostly due to aging and is often associated to the V600E BRAF gene mutation in tumor DNA. Combination of these 3 somatic analyses should reduce indications of germ-line mutation analysis in Lynch syndrome.