Hereditary Non-polyposis Colorectal Carcinoma Syndrome (HNPCC)
Supplemental Studies
- Current definition requires evidence of dysfunctional germ line mutations in DNA mismatch repair enzymes
- We prefer to evaluate both PCR based microsatellite repair instability (MSI) / stability (MSS) and intact / absent immunohistochemical expression of DNA mismatch repair enzymes
- Genetic counseling should be offered before genetic or immunohistologic testing is performed
- PCR test evaluates 5 microsatellites in neoplastic vs. normal tissue
- If ≥2 are altered, designate as MSI-high (MSI-H)
- If one is altered, designate as MSI-low (MSI-L)
- If none altered, designate as MSS
- If more than 5 microsatellites evaluated, alter criteria proportionally
- Immunohistochemical test evaluates presence of mismatch repair enzymes
- It does not evaluate presence of functional enzyme
- Miss-sense mutations may result in an immunohistochemically positive result but a non-functional enzyme
- Most commonly evaluated enzymes are MLH1, MSH2 and PMS2 and may include MSH6
- PMS2 requires MLH1 expression, thus may be absent if MLH1 is lost
- MSH6 requires MSH2 expression, thus may be absent if MSH2 is lost
- Clear absence of an enzyme is abnormal
Familial | Sporadic | |
Immunohistologic loss of MLH1 and PMS2 | May occur | Virtually all |
Immunohistologic loss of MSH2 or MSH6 | May occur | Very rare |
MSI-H | Yes | Yes |
Germline mismatch gene mutation | Yes | No |
MLH1 genetic defect | Most are nonsense or frame shifts | Most are promoter methylation |
BRAF mutation | Rare | Yes |