Consensus molecular subtypes define distinct evolutionary trajectories of biliary tract cancers
Beaudry, F. E. G.; Yendi, D.; Arshinoff, D.; Light, N.; Perrotti, S.; Winter, E.; Cristant, L. R.; Xu, A.; Wilson, J.; Dodd, A.; Bucur, R.; Chen, E. X.; Elimova, E.; Wong, R.; Mesci, A.; Hosni, A.; Ghanekar, A.; Jang, R.; Shwaartz, C. G.; Reichman, T.; Moulton, C.-A.; Sanz Garcia, E.; O'Kane, G. M.; Tsang, E. S.; Wang, X.; McGilvray, I.; Gallinger, S.; Pugh, T. J.; Sapisochin, G.; Vogel, A.; Knox, J. J.; Notta, F.; Grant, R. C.
Show abstract
Biliary tract cancer (BTC) comprises a family of rare malignancies subclassified by anatomy and pathology. However, this scheme may obscure shared biology and limit patient stratification. We therefore performed whole-genome and transcriptome sequencing of 169 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). CCS segregates with anatomical location of primary tumor and expressed gene marker analyses suggest subtypes reflect tumor cell of origin differences. CCS display strikingly divergent molecular landscapes, explaining more variance than anatomical location of primary tumor. CCS-B tumors are mutationally loaded with clock-like and APOBEC signatures and extrachromosomal DNA, whereas CCS-A tumors are characterised by chromosome-arm deletions and higher levels of subclonality. We show harnessing the genomic and transcriptomic diversity of BTC uncovers novel biology and improves stratification. SignificanceWe provide evidence that biliary tract consensus cancer subtypes define fundamentally different cancers, with diverging modes of evolution stemming from distinct cells of origin
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