Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• DNA mismatch repair (MMR) deficiency leads to a mutator phenotype and high-frequency microsatellite instability (MSI-H).
• MSI-H is a key characteristic of Lynch syndrome tumors, caused by germline mutations in MMR genes or MLH1 epimutation.
• MSI-H is also found in sporadic cancers (e.g., colorectal, gastric, endometrial) due to hMLH1 promoter hypermethylation.

Purpose of the Study:

• To review recent advances in microsatellite instability (MSI) research.
• To highlight the significance of MSI-H in understanding tumor biology and clinical features.
• To emphasize the role of MSI-H as a biomarker for Lynch syndrome screening, prognosis, and chemotherapy efficacy.

Main Methods:

• Literature review of recent advances in MSI research.
• Analysis of genetic, epigenetic, and transcriptomic differences in MSI-H versus MSI-stable cancers.
• Comparison of MSI-H characteristics in Lynch syndrome versus sporadic cancers.

Main Results:

• MSI-H cancers exhibit distinct genetic and phenotypic differences compared to MSI-stable cancers, regardless of origin.
• BRAF V600E mutation is linked to sporadic MSI-H colorectal cancers with hMLH1 methylation, but not Lynch syndrome-related ones.
• These molecular differences correlate with distinct biological and clinical features.

Conclusions:

• MSI-H is a crucial indicator of distinct tumorigenic pathways with significant biological and clinical implications.
• Diagnosing MSI-H is increasingly relevant for identifying Lynch syndrome, predicting prognosis, and guiding treatment decisions.
• Further research into MSI-H mechanisms and applications continues to advance cancer diagnostics and therapeutics.