In-silico analysis of MHC genes in hereditary colorectal cancer shows identical by state SNP sharing affecting HLA-DQB1 binding groove

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ABSTRACT Background The role of Human Leukocyte Antigen (HLA) alleles in colorectal cancer susceptibility, development and progression is the focus of ongoing scrutiny. MHC polymorphisms in a Sudanese family with hereditary colorectal cancer were studied using an in silico approach and the results were verified using The Cancer Genome Atlas (TCGA). In this family study, we tested for sharing of nucleotide polymorphisms identified by whole exome capture in major histocompatibility complex region and carried out in-silico prediction of their effects in tumor and control samples. SNPs were analyzed to highlight identical by state sharing, to identify runs of homozygosity, as well as to predict structural and functional effects using homology modeling, damaging effect predictions, and regulatory changes prediction. Results MHC II area showed significantly high degree of homozygosity in tumor samples. Non-synonymous SNPs shared identical by state (IBS) between tumor samples were predicted to affect HLA-DQB1 binding groove. A similar haplotype of these SNPs was identified in a TCGA colonic adenocarcinoma tumor sample. No significant regulatory effects (in the form of transcription factor or miRNA binding site variants) were predicted. Conclusions The results demonstrate IBS SNP sharing of markers affecting HLA-DQB1 binding specificity and probable loss of heterozygosity in MHC II region in colorectal cancer. The significance of this sharing in cancer pathogenesis remains to be established.

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