One shortcoming of this study is that it did not examine for pathogenic DNA alterations in the PMS2 and MSH6 genes; carriers of mutations in these 2 genes might have fallen into their <50-years-old category.
The MMR proteins form heterodimers as part of the base-excision repair complex, with MLH1 pairing with PMS2 and MSH2 pairing with MSH6.
2] Human genes: CAPN9, calpain 9; MLH1, mutL homolog 1; MSH2, mutS homolog 2; MSH6, mutS homolog 6; PMS2
postmeiotic segregation increased 2 (S.
Tissue Microarray Construction and IHC Staining Procedure for Ki-67, MLH1, MSH2, MSH6, and PMS2
Immunoperoxidase stains for Ki-67, MLH1, MSH2, MSH6, and PMS2 were applied to 5-[micro]m-thick, formalin-fixed, paraffin-embedded sections of the tissue microarrays after deparaffinization and rehydration.
A 2-antibody approach (PMS2
and MSH6) can also be employed because MLH1 and MSH2 defects will be detected by secondary loss of PMS2
About 90% of these mutations involve either MLH1 or MSH2 and less frequently can involve other MMR genes, including MSH6 and PMS2
42) Genes more commonly associated with MSI include MSH2 (60%), MLH1 (30%), MLH3, MSH6, PMS1, and PMS2
28) Although loss of MSH2, MSH6, or PMS2
expression is quite strongly correlated with Lynch syndrome, loss of MLH1 expression is more likely to represent acquired methylation of the MLH1 promoter than Lynch syndrome with heritable mutation.
If DNA MMR IHC has not been performed, this testing should be recommended for any cases that show an MSI-H phenotype because this information will help identify the gene that is most likely to have a germline mutation (eg, a patient whose tumor shows loss of MSH2 and MSH6 expression, but retention of MLH1 and PMS2
expression, is likely to have an MSH2 germline mutation).
38-40) MLH1 and MSH2 gene mutations together account, in equal proportion, for 85% to 90% of Lynch syndrome cases among families (41); MSH6 germ line mutations are found in 10% to 15% of cases (42); and rarely, mutations in the PMS2
gene are involved.
Germline mutations in several human DNA mismatch repair genes, including MSH2, MLH1, PMS1, PMS2
, and MSH6/GTBP, have been identified in patients with hereditary nonpolyposis colorectal cancer (HNPCC).