Next-Generation Sequencing Identifies Novel Germline Mutations in Patients with Budd-Chiari Syndrome-Associated Hepatocellular Carcinoma

Abstract

Introduction: Budd-Chiari syndrome-hepatocellular carcinoma (BCS-HCC) is uncommon and its molecular pathogenesis is poorly understood. In this study, we aimed to investigate the genomic landscape of BCS-HCC through whole exome sequencing (WES) to elucidate the cellular and molecular pathways involved in its pathogenesis.

Methodology: We enrolled BCS-HCC (n = 13) and BCS alone (n = 73) patients. WES was performed using the Twist Comprehensive Exome kit on the Illumina platform, followed by quality checks and analysis using the GATK pipeline. Pathogenic/likely pathogenic variants were filtered out from the exonic part of the annotated variant calling file. rsIDs and Cosmic IDs (catalogue of somatic mutations in cancer) were assigned using dbSNP and Cosmic ID databases. Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene ontology analysis were done for pathogenic gene variants.

Results: We observed 1849 significant mutations in 305 genes in BCS-HCC patients, including missense, Indel, and frameshift mutations. Missense variants were more common than frameshift and indels in all subjects. The pathogenic mutations were found in 34 genes-cancer-causing (18 genes) and disease-causing (16 genes, both BCS or BCS-HCC) as per COSMIC cancer gene census. Pathogenic mutations were frequently observed in the mucin family genes including MUC3A, MUC4, MUC6, and MUC16 in BCS-HCC subjects. Changes in extracellular matrix and glycosylation were observed in gene ontology analysis of the genes having pathogenic variants.

Conclusion: Mutations in the mucin gene family including other cancer-causing genes were associated with BCS-HCC in our cohort. Larger, multicentric studies with regional and ethnic diversity are required to validate these findings.

Keywords: BCS; Genes; HCC; Mucin; Pathogenic variants; Sequencing; Tumors.