ИСТИНА

Allele-specific expression (ASE) of germline variants generally represented by single nucleotide polymorphisms (SNPs) is known to be associated with some hereditary disorders. ASE has been reported to occur in several types of tumors but the data on its mechanisms and contribution of particular variants are scarce and virtually no systematic research on ASE in hepatocellular carcinoma (HCC) has been carried out to date. Using whole exome and transcriptome sequencing data on 5 paired liver-HCC samples and matched metastases we identified 582 differentially expressed germline variants including common up-regulated variants with shared ASE pattern across samples and 56 rare SNPs in protein-coding genes with minor allele frequency < 5% generally represented by putatively deleterious variants. In silico profiling of genes that demonstrate ASE revealed enrichment in genes that fall within GO categories “DNA binding” and “IGF1 pathway”. Despite previous reports, we observed uneven distribution of up-regulated variants with the majority being located at chromosomes 1, 6, 16 and 19. Cytogenetic band enrichment analysis revealed that there were extensive regions comprising unanimously regulated allele-specifically expressed genes. Although a primary tumor and metastasis preserve similarity in allelic expression, certain variations observed in allele-specific pattern of gene expression as the result of tumor progression to metastatic phenotype provide an insight into the dynamic and coordinated nature of the process when SNP-containing genes located in a specified chromosome region demonstrate shared and proportional change of allelic expression. Our results imply that ASE of germline SNPs may confer susceptibility to HCC and favor tumor progression. Experimental validation of the data on variants and mechanisms underlying ASE in HCC is currently carried out. The work was partially supported by Russian Ministry of Education and Science contract 14.607.21.0049, RFMEFI60714X0049.