Association of Functional Polymorphisms in MSH3 and IL-6 Pathway Genes with Different Types of Microsatellite Instability in Sporadic Colorectal Cancer

Author:

Salar Anamarija1,Vuković Đerfi Kristina1,Pačić Arijana2ORCID,Škrtić Anita3ORCID,Cacev Tamara1ORCID,Kapitanović Sanja1ORCID

Affiliation:

1. Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia

2. Department of Pathology and Cytology, University Hospital Dubrava, 10000 Zagreb, Croatia

3. Department of Pathology and Cytology, University Hospital Merkur, 10000 Zagreb, Croatia

Abstract

Microsatellite instability (MSI) has been recognized as an important factor in colorectal cancer (CRC). It arises due to deficient mismatch repair (MMR), mostly attributed to MLH1 and MSH2 loss of function leading to a global MMR defect affecting mononucleotide and longer microsatellite loci. Recently, microsatellite instability at tetranucleotide loci, independent of the global MMR defect context, has been suggested to represent a distinct entity with possibly different consequences for tumorigenesis. It arises as a result of an isolated MSH3 loss of function due to its translocation from the nucleus to the cytoplasm under the influence of interleukin-6 (IL-6). In this study the influence of MSH3 and IL-6 signaling pathway polymorphisms (MSH3 exon 1, MSH3+3133A/G, IL-6-174G/C, IL-6R+48892A/C, and gp130+148G/C) on the occurrence of different types of microsatellite instability in sporadic CRC was examined by PCR–RFLP and real-time PCR SNP analyses. A significant difference in distribution of gp130+148G/C genotypes (p = 0.037) and alleles (p = 0.031) was observed in CRC patients with the C allele being less common in tumors with di- and tetranucleotide instability (isolated MSH3 loss of function) compared to tumors without microsatellite instability. A functional polymorphism in gp130 might modulate the IL-6 signaling pathway, directing it toward the occurrence of microsatellite instability corresponding to the IL-6-mediated MSH3 loss of function.

Funder

Croatian Science Foundation

Publisher

MDPI AG

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