Table 3. Similarities and disparities between mice and men suffering from MLH1 inactivation and accordingly MMR-D.
| MLH1 loss and functional consequences | ||||
|---|---|---|---|---|
| characteristic | Lynch Syndrome | CMMR-D | homozygous knockout mouse model | |
| clinicopathological characteristics | frequency of the underlying mutation among MMR defects | >40% | ~20% | - |
| mean age of onset | 42.4 yrs [37] | 7.5 yrs [42] | 3.8 months (lymphoma), 8.0 months (GIT) [20 and own observations] | |
| tumor incidence | high, >80% | high, 100% | high, >80% | |
| tumor spectrum | diverse (large and small bowel, endometrium, stomach, kidney, brain) | LS-associated tumors > hematological malignancies> brain tumors | LS-associated tumors ≥ hematological malignancies > others (skin) | |
| metastastic spread | infrequently, syn-or metachronous tumorigenesis is more frequent [26, 37] | yes, very frequent in various organs [42, 43] | not in GIT, only described for lymphomas | |
| MHC class I expression | lost in 30-40% primarily due to β2-microglobulin mutations [35] | unknown | 100% positive | |
| MSI in mononucleotide repeats | high [27] | divergent results dependent on tumor location and marker panel used to determine MSI (low > high) | high | |
| MSI in coding regions of genes | high, several driver mutations are described (e.g. TGFBR2, AIM2, HT001 and ACVR2A, [27]) | largely unknown, one report on TGFβR2 mutations in a PMS2-/- case [44] | some candidate target genes described (Rfc3, Senp6, Phactr4, only GIT, [10]), novel: Tmem60 and Rasal2 (GIT and lymphoma), Nktr1, C8a, Taf1b, and Lig4 (only GIT) | |
| karyotype | near-diploid with few, if any, karyotypic abnormalities [14, 26] | unknown | near-diploid with few, if any, karyotypic abnormalities (as determined by flow cytometric ploidy analysis) | |
| drug response and radiosensitivity | common cytostatics | conflicting results, from high response towards 5-FU > complete resistance, but: good response to oxaliplatin and irinotecan [14, 39] | less known, drug-specific response (GIT and brain tumors seems worse, partial response, if any, while hematological malignancies showed principally good response [11]) | resistance against 5-FU, good response towards Oxaliplatin and Irinotecan |
| methylating/ alkylating agents | resistant [39] | resistant (especially O6-methylating agents, like temozolomide [43]) | resistant against SN1 and O6-meythlating agents | |
| radiation | conflicting results, from no response to good or even better response compared to MMR-proficient tumors (primarily indicated for MMR-D associated rectal cancers (= 8% of all MLH1-/- associated tumors) [40] | radioresistance shown for most of the brain tumors (some with partial response), CRCs do also not seem to respond (partial remission with short recurrence), no large studies on hematological malignancies [11] | less sensitive than MMR-proficient cells, but not completely resistant | |
| tumor microenvironment | cytotoxic T- cell infiltration | high, most of them are activated, primarily clustering at the tumor invasive front [38] | unknown | high, infiltration increases from adenoma > carcinoma |
| T helper cell infiltration | moderate-high, usually co-localizing with CD8+ T cells and/or antigen-presenting cells [38] | unknown | detectable in varying degree, but, if present, primarily clustering at the tumor invasive front | |
| NK cell infiltration | high, especially in MHC I negative tumors, supposed to be involved in controlling metastasis | unknown | low > absent | |
| expression of immune checkpoint proteins | highly upregulated (PD-1, CTLA-4, IDO, LAG-3 in TIL, stroma and invasive front compartments [18, 41]) | undescribed, but supposed to be upregulated due to high mutational load and response to PD-L1 blockade [44] | high expression of CTLA-4 and IDO on tumor cells, upregulated PD-L1 and PD-1 expression in stroma and TIL, but low expression of LAG-3 | |
TIL - tumor-infiltrating lymphocytes; GIT - gastrointestinal tumor; novel findings are highlighted in bold