Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma

Abstract

We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.

The Origins and Consequences of Localized and Global Somatic Hypermutation

“…Genome instability is one of the hallmarks of cancer, and cancer is often referred to as a "disease of the genome" 1 . Just as cancers are heterogeneous over time and space [2][3][4] , they are also heterogeneous in the number of mutations they harbour --their "mutational density". Some tumour types, like melanomas and lung cancers, harbour hundreds of thousands or even millions of single nucleotide variants (SNVs).…”

Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine?

“…In addition, new oncogenic events can occur in the metastatic tumours that contribute to a different profile. Interestingly, Dong et al observed new mutations in the recurrence which were not present in the primary tumour and were known to be associated to chemo‐resistance …”

“…In line with this hypothesis, multiregional sequencing studies have recently shown that parallel evolution and chromosomal alteration can shape spatial heterogeneity and promote branch diversity in iCCA. 45 The availability of tissue from the primary and the recurred tumour in one case allowed Dong et al to assess the temporal evolution of iCCA. 45 Multiple mutational clusters were present at a subclonal occurrence in more than one area in the recurrent tissue, indicating a polyclonal metastatic seeding pattern in CCA ( Figure 2).…”

“…45 The availability of tissue from the primary and the recurred tumour in one case allowed Dong et al to assess the temporal evolution of iCCA. 45 Multiple mutational clusters were present at a subclonal occurrence in more than one area in the recurrent tissue, indicating a polyclonal metastatic seeding pattern in CCA ( Figure 2). We can then speculate that two or more primary clones can be responsible for metastatic progression, either because a synergistic co-operation between the clusters may prove beneficial in the evolutionary dynamics or because an early colonization may remodel the microenvironment to facilitate colonization of further clones.…”

“…In addition, new oncogenic events can occur in the metastatic tumours that contribute to a different profile. Interestingly, Dong et al observed new mutations in the recurrence which were not present in the primary tumour and were known to be associated to chemo-resistance 45. Taken altogether, these data underline the importance of understanding the molecular landscape of advanced CCA in order to be able to develop novel effective therapeutic strategies.…”