Gene profiling using whole genome analysis of bile tract cancer and its association with clinical factors

Background: Bile tract cancer (BTC) is a malignant tumor with poor prognosis. The genetic background and molecular profiles of BTC remain poorly understood. Objective: To clarify the genetic diversity of BTC using whole-genome analysis and identify gene mutations as targets for novel diagnostic and therapeutic approaches. Methods: Whole-genome sequencing was performed using paired tumor and normal tissue samples from 7 patients with BTC who underwent surgery at our institution. Somatic mutations were detected and annotated using snpEff. Oncoplot analysis visualized mutation accumulation patterns, and associations with clinical factors including lymph node metastasis, vascular invasion, neural invasion, portal vein invasion, and IPNB. Results: On classification of detected somatic mutations, annotation revealed that intergenic region mutations (mean: 31,085, range: 26,588-39,135) were most frequent. Frameshift variants (mean: 16.7, range: 11-25), splice donor/acceptor variants (mean: 34.3, range: 17-45), and stop gained mutations (mean: 7.4, range: 2-10) were identified as important functional mutations. In addition, missense variants (mean: 529.4, range: 363-647) were also identified. Regarding nonsynonymous mutations, missense mutations were most common in variant classification, and SNPs (single nucleotide polymorphisms) were most frequent in variant type. Among SNV classes, T to G and C to T transitions were highly identified. Thirty genes, including MUC16 and MUC6, were identified with mutations in 3 or more of the 7 cases. Oncoplot analysis of these genes suggested that mutations accumulated more extensively and were associated with tumor mutation burden (TMB) in samples without vascular invasion. In contrast, no accumulation patterns of mutations were observed concerning lymph node metastasis, neural invasion, portal vein invasion, or IPNB. Among the genes (331 mutations, 321 genes) registered in The Cancer Genome Atlas (TCGA) bile duct cancer database, our study identified MUC16, OBSCN, and TP53. However, no overlap in their mutations was observed. It suggests extremely high genetic heterogeneity in BTC. Conclusion: BTC is characterized by a high mutational burden and genetic diversity. An association between vascular invasion status and mutation accumulation was suggested. Gene profiling is considered important for personalized medicine, and the identified gene mutations may serve as potential targets for novel diagnostic and therapeutic approaches.