Differences and evolution of the methods for the assessment of microsatellite instability

Abstract

Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di-or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono-and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under-or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.

Variations in short tandem repeats deduced on the basis of the number of repeats and the relationship of these variations with longevity

“…STRs are named according to the number of repeats; different STR alleles can occur in a single STR locus, thereby resulting in STR polymorphism. Generally, an STR polymorphism is considered the result of gene mutation (Butler 2006;Eckert and Hile 2009;Laghi et al 2008). Accordingly, an STR with the highest frequency distribution in a certain population is considered a conservative STR, and an STR with relatively low or very low frequency distribution is considered a result of gene mutation and natural selection.…”

Therapeutic Targeting of the DNA Mismatch Repair Pathway

“…3 Inhibition of PINK1 in an MMR-deficient background results in an elevation of reactive oxygen species and the accumulation of both nuclear and mitochondrial oxidative DNA lesions. Taken together, these data highlight the potential for focusing upon oxidative damage as a therapeutic target in MMR deficiency.…”

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

“…BAT26 and BAT25 loci were amplified by fluoresceinated primers, and PCR products analyzed by capillary electrophoresis (ABI PRISM 310 DNA Sequence; PE Applied Biosystems). The MSI phenotype (high-MSI) was defined by the appearance of shorter alleles at BAT26 and/or at BAT25 (25).…”