Disease relevance of MSH2

• METHODS: We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer [1].
• We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing [1].
• Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable [2].
• This trend was also found in MSH2-deficient human endometrial cancer cells (HEC59) when compared with HEC59/2-4 (hMsh2-corrected) cells [3].
• Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer [4].
• We previously described a founder mutation, MSH2*1906G >C (A636P) that causes HNPCC in 8/1345 (0.59%) of Ashkenazim with colorectal cancer [5].

Psychiatry related information on MSH2

• RESULTS: Genetic counseling revealed a variety of findings characterized by emotional stress in MSH2 germline mutation carriers [6].

High impact information on MSH2

• We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC [7].
• We identified ten different germline MLH3 variants, one frameshift and nine missense mutations, in 12 patients suspected of HNPCC [7].
• These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, whereas mutations in MSH3 and MSH6 are rare [8].
• Involvement of nucleotide-excision repair in msh2 pms1-independent mismatch repair [9].
• RESULTS: Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent) [1].

Chemical compound and disease context of MSH2

• MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart [10].
• Induction of two DNA mismatch repair proteins, MSH2 and MSH6, in differentiated human neuroblastoma SH-SY5Y cells exposed to doxorubicin [11].
• MSH2 codon 322 Gly to Asp seems not to confer an increased risk for colorectal cancer susceptibility [12].
• In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)] [13].
• A decreased expression level of up to 80% of mRNAs encoding hMLH1 and hMSH2 was observed in drug-resistant melanoma cells selected for cisplatin, etoposide and fotemustine, while vindesine-selected cells showed only moderate reduction [14].

Biological context of MSH2

• BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern [15].
• The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations [16].
• Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6 [17].
• Notably, a deletion encompassing exons 1-6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder [18].
• Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p [19].

Anatomical context of MSH2

• Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1 [1].
• Extracts of immortalized MSH2-deficient mouse fibroblasts did not correct most single base mispairs [20].
• Our data demonstrate that the MutSalpha (MSH2/MSH6) complex binds specifically to DNA containing an IdUrd-G mismatch, using both purified human MutSalpha as well as nuclear extracts from Msh2-proficient and-deficient mouse cell lines [21].
• CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered [22].
• MSH2-/- and MSH2+/+ embryonic stem cells were established as xenografts in athymic nude mice [23].

Associations of MSH2 with chemical compounds

• These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG [24].
• Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide [25].
• MSH2-/- tumors were significantly less responsive to cisplatin than MSH2+/+ tumors, whereas there was no difference in sensitivity to oxaliplatin [23].
• Consistent with our recent publication, coadministration of IdUrd and a chemical inhibitor of BER, methoxyamine (MX), also increases the extent of MSH2 nuclear colocalization with IdUrd [21].
• We have previously demonstrated that both the MLH1 and MSH2 status impact the DNA levels of the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd), and thereby radiosensitization induced by these analogues, indirectly implicating both mismatch repair (MMR) proteins in the removal of these bases from DNA [21].

Physical interactions of MSH2

• As a rule, MSH2 is primarily complexed with MSH6 [26].
• The EXO1 gene was identified in Saccharomyces cerevisiae as a gene encoding an exonuclease that interacts with MSH2 and functions in mismatch repair and genetic recombination [27].
• Both the number of RAD51 foci and the amount of the BLM-p53-RAD51 complex are increased in hMSH2- or hMSH6-deficient cells [28].
• Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6 [29].
• Finally, both Chk1 and Chk2 interact with the MMR protein MSH2, and this interaction is enhanced after MNNG exposure, supporting the notion that the MMR system functions as a molecular scaffold at the sites of DNA damage that facilitates activation of these kinases [30].

Regulatory relationships of MSH2

• In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2 [31].
• MSH2 was expressed in all stages of spermatogenesis up to but excluding mature sperm whereas MLH1 was predominantly expressed in premeiotic germ cells [32].
• We show here that upon UV irradiation p53 activates transcription of the human mismatch repair gene MSH2 [33].
• Importantly, depletion of endogenous Bcl2 by RNA interference enhances formation of the hMSH2-hMSH6 complex in association with increased MMR and decreased mutagenesis [34].
• Western blot analysis and immunohistochemistry demonstrated that hMLH1 and hPMS2 are widely expressed nuclear proteins with a distribution pattern very similar to that previously described for hMSH2 [35].

Other interactions of MSH2

• In contrast, in cells that overexpress MSH3, the available MSH2 protein is sequestered predominantly into MutSbeta [26].
• By Western blotting analysis, we found cell lines that are deficient or decreased in the amount of MSH6, or PMS2, or MSH2 proteins [36].
• In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2 [37].
• We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo [38].

Analytical, diagnostic and therapeutic context of MSH2

• METHODS: We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families [16].
• We investigated 100 unselected GCTs and 11 clinically defined chemotherapy-resistant GCTs for MSI using 8 mono- or dinucleotide markers and the presence of the mismatch repair factors MLH1, MSH2, and MSH6 by immunohistochemistry [39].
• The simplicity and rapidity of their detection, using fluorescent multiplex PCR, led us to recommend to begin the molecular analysis in HNPCC by screening for MSH2 rearrangements [40].
• Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications) [41].
• High-performance liquid chromatography analysis of IdUrd and BrdUrd levels in DNA suggests that this differential cytotoxicity may be due to lower analogue levels in MSH2+ murine and human tumor cells [3].

References