Utilization of microsatellites for the analysis of genomic alterations in colorectal cancers in Brazil

Abstract

Two different pathogenetic mechanisms are proposed for colorectal cancers. One, the so-called "classic pathway", is the most common and depends on multiple additive mutational events (germline and/or somatic) in tumor suppressor genes and oncogenes, frequently involving chromosomal deletions in key genomic regions. Methodologically this pathway is recognizable by the phenomenon of loss of heterozygosity. On the other hand, the "mutator pathway" depends on early mutational loss of the mismatch repair system (germline and/or somatic) leading to accelerated accumulation of gene mutations in critical target genes and progression to malignancy. Methodologically this second pathway is recognizable by the phenomenon of microsatellite instability. The distinction between these pathways seems to be more than academic since there is evidence that the tumors emerging from the mutator pathway have a better prognosis. We report here a very simple methodology based on a set of tri-, tetra-and pentanucleotide repeat microsatellites allowing the simultaneous study of microsatellite instability and loss of heterozygosity which could allocate 70% of the colorectal tumors to the classic or the mutator pathway. The ease of execution of the methodology makes it suitable for routine clinical typing.

Microsatellite instability affecting the T17 repeats in intron 8 of HSP110, as well as five mononucleotide repeats in patients with colorectal carcinoma

“…For example, BAT-26 is most sensitive to detection because of its small unstable alleles that are easily distinguished from normal ones either by single-strand conformation polymorphism or sequencing [28]. Some groups relied only on BAT-25 and BAT-26 when examining the MSI status of CRC due to their high sensitivity, instead of assessing the entire NCI panel [28]. We also found that BAT-25 and BAT-26 are most easily detected in MSI-H CRC due to the 100% sensitivity.…”

Low expression of MSH2 DNA repair protein is associated with poor prognosis in head and neck squamous cell carcinoma

“…It represents the 6 th most common type of human cancer, and it is responsible for high death rates worldwide every year 4,10 . A plethora of sociodemographic, economic, and cultural factors are associated with the development of HNSCC, along with a background of molecular disturbances, both genetic and epigenetic, that influence the course and incidence of the disease 1,8 .…”

Polymorphic variation of mononucleotide microsatellites in healthy humans and its implication for microsatellite instability screening

“…Thus, analysis of only tumoral tissue without comparison with the corresponding normal tissue has been proposed and considered suffi cient for instability detection in patients at risk for HNPCC by many authors (8,9,20) . In addition, since small unstable alleles can be easily distinguished from normal ones by SSCP (single strand conformation polymorphism) or sequencing, and BAT-26 is highly sensitive to detect MSI-H colorectal tumors, some investigators have proposed that analysis of BAT-26 alone can determine MS status in CRCs with greater than 99% accuracy (2,4,6,7,19) . Therefore, many published reports have determined MS status using only tumoral tissue and the two markers BAT-25 and BAT-26 instead of the panel of 5 markers originally recommended by the National Cancer Institute (NCI) (9,10,20) .…”

“…Therefore, allelic variation of these markers in specifi c populations should be determined before a decision is made on the most reliable clinical protocol for MSI screening. Little has been published on MS status in sporadic and hereditary CRC in Brazilian patients and healthy individuals (7) .…”