MSH2 forms a heterodimer with MSH6, while MLH1 binds to PMS2 and complexes MSH2/MSH6 heterodimer. Therefore, when MSH6 is not detected in a tumour MSH6 may also not detected. The situation is more complex with lack of MLH1 expression. Hypermethylation of hMLH1 gene, which is common in sporadic colorectal cancer, may lead to loss of protein expression. IHC has a role in detecting MMR defects, with data suggesting that the effectiveness of IHC screening of the MMR proteins would be similar to that of the more complex strategy of microsatellite genotyping (23,25). This technique can guide which Inhibitors,research,lifescience,medical gene to sequence and can help differentiating

sporadic from hereditary mutations: MSH2 loss is likely to be HNPCC, whereas MLH1 loss could be HNPCC or sporadic CRC (MLH1 promoter methylation). MMR proteins Inhibitors,research,lifescience,medical heterodimerize

to function; the MSH2 loss almost always accompanies MSH6 loss and when MLH1 is lost, generally so is hPMS2 (35,36). In addition, IHC can miss functional loss; i.e. presence of the protein with antigen positivity in the absence of function. MMR IHC studies are based on a complete absence of at least one MMR protein (37-41). But these studies do not consider the immunostaining Inhibitors,research,lifescience,medical topographic heterogeneity. Since the MMR proteins function as heterodimers, it could be advocated to validate the IHC results of MSH2/MSH6 and MLH1/PMS2. More studies are required to clarify the influence of this predictable tumor heterogeneity to select the appropriate sample for immunohistochemical and/or MSI VRT752271 cost analyses Genetic testing Multiple methods Inhibitors,research,lifescience,medical have been used for genetic testing in HNPCC. The methods used should ideally be able to detect the many potential genotypes associated Inhibitors,research,lifescience,medical with HNPCC like nonsense, missense, and frame shift mutations, genomic deletions, duplications, and rearrangements. The commonly used tests includes: high output screening techniques, DNA sequencing, conversion analysis and methods to detect large structural DNA abnormalities

like Southern blot and Multiplex ligation-dependent probe amplification. Aims Information about MMR protein status in colorectal cancer is important because it will identify those most likely to have Lynch syndrome and those most likely to have microsatellite instability in their tumours which has been proven to have better prognosis and may affect their treatment regimens in the future. We next undertook this study to develop and optimise a protocol for MMR protein immunohistochemistry testing in colorectal cancer. We also aimed to analyse the proportion of patients with colorectal cancer with loss of immunostaining for MMR proteins (hMLH1, hMPS2, hMSH2 and hMSH6) in order to determine the feasibility of molecular screening for the loss of MMR proteins through the study of unselected patients with colorectal cancer.