What genetic abnormalities point to HNPCC?
HNPCC presents in a younger age group and has an autosomal dominant pattern of inheritance. Revised Bethesda Criteria are set to screen the patients for MSI. DNA mismatch repair (MMR) gene defect is tested for hMLH1 (50%), hMSH2 (39%), hMSH6 (8%), and hPMS2 (1%) genes. These defects result in insertion or deletion of nucleotides in the microsatellite sequences, which are tested using PCR and reported as high (MSI-H), low (MSI-L), or stable (MSS). At least five microsatellite sequences are tested and MSI-H is defined as instability in 30% to 40% of markers (two of five at least).
- • Loss of hMSH2 indicates HNPCC.
- • Loss of hMLH1 indicates HNPCC or sporadic CRC (loss caused by hypermethylation of hMLH1 promoter in sporadic CRC).
- • The IHC on paraffin sections (of normal and tumor) to test for mismatch repair is also done, which shows loss of staining in the tumor (caused by mutated gene) compared with the normal. Loss of hMSH2 and/or hMSH6 is highly associated with Lynch syndrome. Direct gene sequencing can be done in highly susceptible cases and to confirm the results of MSI and IHC. A negative test in an at-risk patient does not rule out other hereditary causes of CRC.