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Intratumor heterogeneity of microsatellite instability in sporadic colorectal cancer

2Department of Pathology, Clinical Hospital Dubrava, Zagreb, Croatia Background: Microsatellite instability (MSI) status has become an important factor in colorectal cancer (CRC) therapeutic decisions due to novel targeted therapies including immune checkpoint inhibitors. Recently, a new form of microsatellite instability, elevated microsatellite instability at selected tetranucleotides (EMAST) has been described leading to possible speculations about its role in CRC development and progression. Intratumor heterogeneity (ITH) is a phenomenon that arises from evolutionary dynamic of tumor progression leading to the clonal expansion of different clones within the tumor with different responses to antitumor therapy. Previous CRC heterogeneity studies have mainly focused on major mutations such as KRAS and TP53 while the data regarding the microsatellite instability is scarce. Materials and methods: In this study we have examined the possible ITH of MSI/EMAST status in 30 sporadic CRCs. In four tumor sections and corresponding normal mucous tissue MSI status was examined using the conventional Bethesda panel while EMAST status was established using five tetranucleotide microsatellite markers (MYCL1, D2S82, D2S85, D8S321 and D9S252). Targeted loci were amplified by PCR and analyzed either by polyacrylamide gel electrophoresis or GeneScan analysis. Results: In MSI and EMAST positive tumors instability was present in all tumor specimens, but with different instability profiles in one tumor. Tumors positive only for EMAST presented with more uniform pattern. The most unstable markers were D17S250, MYCL1 and D20S82. Conclusion: In this preliminary study we have shown that MSI affects the ITH profile of MSI/EMAST positive tumors.

colorectal cancer ; microsatellite instability ; MSI, ; EMAST ; tumor heterogeneity

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