Integrated Whole-Genome and Transcriptome Sequencing Reveals Divergent Evolutionary Processes Across Biliary Tract Cancer Subtypes

Biliary tract cancer (BTC) comprises a family of rare malignancies subclassified by anatomy and pathology. However, this classification scheme may obscure shared biology and limit patient stratification. Here, we tested whether BTC heterogeneity can be explained by coherent latent axes and evaluated the potential to unify diverse clinical and genomic factors under a tractable biological framework. Whole-genome and transcriptome sequencing was performed on 180 tumors enriched for tumor cells by laser capture microdissection to identify shared programs in BTC. Network integration across transcriptomic classes identified two consensus cancer subtypes (CCS). The CCS segregated with anatomical location of primary tumor, and gene expression marker analyses suggested that subtypes reflect tumor cell of origin differences. The CCS displayed strikingly divergent molecular landscapes, explaining more variance than anatomical location of the primary tumor. CCS-B tumors were mutationally loaded with clock-like and APOBEC signatures and extrachromosomal DNA, whereas CCS-A tumors were characterized by chromosome-arm deletions. This approach showed that harnessing the genomic and transcriptomic diversity of BTC provides insights into shared biology and improves stratification.