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The effect of mismatch repair deficiency on tumourigenesis; microsatellite instability affecting genes containing
J T Johannsdottir1, J G Jonasson, J T Bergthorsson
1Department of Pathology, National University Hospital, Reykjavik, Iceland.
Abstract:
We have investigated microsatellite instability (MSI) in colorectal, gastric, endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI-H). Both insertions and deletions were evident and occasional intratumour heterogeneity was evident with more than one different additional allele in the tumour. Most MSI-H tumours had acquired mutations in more than one gene and longer repeated sequences were more frequently targets for mutations. The TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours and E2F4 polymorphisms was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGFbetaIIR mutations, which were frequently found in colon and gastric tumours but not in endometrial tumours, suggesting that endometrial tumours progress by a different route where TGFbetaIIR mutations are less favourable.
Insights
Microsatellite instability (MSI) in cancers is linked to mismatch repair (MMR) deficiency, causing mutations in key genes like TGFbetaIIR and hMSH3. Longer repeats and MSI-High tumors showed more mutations, with distinct patterns across cancer types.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Cancer Genomics
Background:
- Microsatellite instability (MSI) is a hallmark of DNA mismatch repair (MMR) deficiency.
- MSI leads to frameshift mutations in genes with repetitive sequences, impacting cell fidelity and growth.
- These mutations are implicated in various cancers, including colorectal, gastric, endometrial, and ovarian.
Purpose of the Study:
- To investigate the spectrum and frequency of gene mutations in MSI-High (MSI-H) tumors across different cancer types.
- To identify specific genes frequently mutated due to MMR deficiency.
- To explore potential differences in mutation patterns between cancer types.
Main Methods:
- Analysis of frameshift mutations in genes such as hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4, and BRCA2.
- Detection of mutations in colorectal, gastric, endometrial, and ovarian tumors exhibiting MSI.
- Assessment of mutation heterogeneity and frequency across different genes and cancer types.
Main Results:
- Frameshift mutations were detected in multiple genes critical for cell fidelity and growth control in MSI-H tumors.
- TGFbetaIIR (62%), hMSH3 (43%), and E2F4 (35%) were among the most frequently mutated genes in MSI-H tumors.
- Mutation accumulation was heterogeneous, often affecting multiple genes, with longer repeats being more susceptible.
- E2F4 mutations were specific to colon tumors, while TGFbetaIIR mutations were prevalent in colon and gastric but not endometrial cancers.
Conclusions:
- MMR deficiency drives significant genetic instability in MSI-H cancers, affecting key regulatory genes.
- Mutation patterns vary by gene and cancer type, suggesting distinct molecular pathways in tumorigenesis.
- TGFbetaIIR mutations may play a differential role in gastric/colon versus endometrial cancer progression.