Background
(A) Sporadic dMMR – MLH1 Promoter Hypermethylation | (B) Lynch Syndrome | (C) Sporadic dMMR – Somatic MMR Mutations | (D) Constitutional Mismatch Repair Deficiency (CMMRD) | |
---|---|---|---|---|
Germline mutation | None | One allele of a MMR gene (MLH1, PMS2, MSH2, MSH6) | None | Both alleles of a MMR gene (MLH1, PMS2, MSH2, MSH6) |
Somatic mutation |
BRAF V600E | 2nd allele of the mutated MMR gene | Both alleles of a MMR gene (MLH1, PMS2, MSH2, MSH6) | None |
Epigenetic alteration | Somatic biallelic promoter methylation of MLH1
| Germline deletion in 3′ end of EPCAM leads to MSH2 methylation | None | None |
Intense Lifelong Screening | No | Yes | No | Yes |
Main text
Sporadic dMMR colorectal cancers – MLH1 promoter hypermethylation/CpG Island Methylator Phenotype (CIMP)
Lynch syndrome
Amsterdam criteria (meet all sub criteria) | Amsterdam II criteria (meet all sub criteria) | Revised Bethesda criteria (meet one of the following sub criteria) |
---|---|---|
3 or more relatives with histologically confirmed colorectal cancer |
3 or more relatives with Lynch syndrome-associated cancer (colorectal cancer or cancer of the endometrium, small intestine, ureter or renal pelvis); cancers are histologically verified | Colorectal cancer diagnosed in a patient aged <50 years |
2 or more successive generations involved |
2 or more successive generations affected | Presence of synchronous, metachronous colorectal cancer or other Lynch syndrome-related tumors: cancer of the colorectum, stomach, small intestine, pancreas, biliary tract, renal pelvis, ureter, ovary, brain; sebaceous gland adenoma or carcinoma and keratoacanthoma, regardless of age |
1 or more of the cancers diagnosed before age 50 years |
1 or more relatives diagnosed before the age of 50 years | Colorectal cancer with MSI phenotype, especially lymphocyte infiltration, diagnosed in a patient aged <60 years |
One should be a first-degree relative of the other two | One should be a first-degree relative of the other two | Patient with colorectal cancer and a first-degree relative with a Lynch syndrome-related tumor, with one of these cancers diagnosed at age <50 years |
Familial adenomatous polyposis should be excluded | Familial adenomatous polyposis should be excluded in cases of colorectal carcinoma | Patient with colorectal cancer with two or more first-degree or second-degree relatives with a Lynch syndrome-related tumor, regardless of age |
Phenotypic variation in LS
Unexplained dMMR colorectal cancers (sporadic dMMR-somatic MMR mutation and others)
Constitutional mismatch repair deficiency syndrome (CMMRD)
Clinicopathologic features of MSI CRC
Screening for MSI and LS
Practical guide for MMR IHC interpretation
MMR sensitivity and specificity
MMR staining patterns
-
In cases of isolated loss of PMS2 IHC, germline MLH1 analysis should be performed if no mutations are detected through PMS2 testing. In a study by Dudley et al [65], approximately 24% of patient with tumors with isolated loss of PMS2 expression harbor germline MLH1 mutation. Furthermore, a subset of MLH1 mutations result in functionally inactive MLH1 protein that is antigenically intact and will be detected by the commonly used anti-MLH1 antibody clones. Such germline MLH1 mutations will lead to decreased MLH1 protein stability and/or quantity, compromised stability of MLH1-PMS2 complexes, and subsequent PMS2 degradation. Recently, Rosty et al. [66] demonstrated similar findings, and they also recommend germline MLH1 mutation analysis in individuals with isolated loss of PMS2 expression but without PMS2 mutation identified.
-
Very rarely, all four stains are lost (null pattern) due to a germline MSH2 mutation (causing absent MSH2/MSH6) together with a somatic MLH1 hypermethylation (causing absent MLH1/PMS2) [67].
-
Another uncommon finding is loss of MSH6 together with MLH1 and PMS2. This could occur due to MLH1 promoter hypermethylation causing MLH1/PMS2 loss, leading to MSI. Such MLH1/PMS2 deficient, MSI tumors, are prone to generate somatic mutations in MSH6 gene, which cause significantly reduced staining of MSH6 [68].