Chromosomal instability and genomic alterations in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a lethal cancer of the bile duct. Several studies have characterized genomic alterations in CCA tumours, and aneuploidy of chromosomes 3, 7, 9p and 17 are indicators of poor prognosis. Nonetheless, little is known if chromosomal instability, the ongoing alteration of the genome that is a feature of most cancers, is present in CCA tumours. In this study, we leveraged a panel of CCA cancer cell lines as well as a matched normal cholangiocyte line as a control, to characterise CCA chromosomal instability. We observed moderate rates of segregation errors compared to highly genomically unstable cancers such as colorectal or ovarian, potentially driven by elevated levels of DNA replication stress and centrosome duplication. Single cell genome sequencing and karyotyping showed high levels of structural and numerical aberrations and copy number alterations that were heterogeneous between individual cells, supporting the notion these cell lines models exhibit ongoing chromosomal instability. Sequencing of thirty-three CCA tumour samples with matched normal tissue similarly showed increased whole and sub-chromosomal level alterations, with a higher extent of genomic alterations in intrahepatic tumours compared to extrahepatic.