| Title | Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma |
| Study Type | Other |
| Abstract |
Identification of genes encoding recurrent mutations, sets of co-mutated genes and their characteristic features are crucial to understand diversity of tumors, which in turn might lead to better understanding for personalized cancer therapies. Here, we analyzed the exomes of 142 intrahepatic chola .. [more]ngiocarcinoma (iCCA) patients alongside targeted screening of 150 additional patients and identified IDH1, KRAS and TP53 as the three most recurrent genes, constituting more than half of patients in our cohort. Grouping patients based on these mutations revealed distinct preferences for mutational signatures, co-mutation profiles and enriched pathways across groups. In vitro screening with 10 selected drugs in 7 cell lines, chosen to mirror patient mutation subgroups, confirmed in silico predictions with greatest inhibitory effects observed in cells enriched in mutations in the targeted pathway. Furthermore, patients lacking all three mutations (‘undetermined group’) have prevalent copy number alterations that encodes genes regulating DNA repair. Our results provide a framework to stratify iCCA patients based on driver mutations and direct therapy appropriately. Finally, we propose that recurrent mutation-based classification of iCCA may be applied to other drug-refractory cancer types to guide therapy. [less]
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| Description |
Identification of genes encoding recurrent mutations, sets of co-mutated genes and their characteristic features are crucial to understand diversity of tumors, which in turn might lead to better understanding for personalized cancer therapies. Here, we analyzed the exomes of 142 intrahepatic chola .. [more]ngiocarcinoma (iCCA) patients alongside targeted screening of 150 additional patients and identified IDH1, KRAS and TP53 as the three most recurrent genes, constituting more than half of patients in our cohort. Grouping patients based on these mutations revealed distinct preferences for mutational signatures, co-mutation profiles and enriched pathways across groups. In vitro screening with 10 selected drugs in 7 cell lines, chosen to mirror patient mutation subgroups, confirmed in silico predictions with greatest inhibitory effects observed in cells enriched in mutations in the targeted pathway. Furthermore, patients lacking all three mutations (‘undetermined group’) have prevalent copy number alterations that encodes genes regulating DNA repair. Our results provide a framework to stratify iCCA patients based on driver mutations and direct therapy appropriately. Finally, we propose that recurrent mutation-based classification of iCCA may be applied to other drug-refractory cancer types to guide therapy. [less]
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| Center Name | Biotech Research and Innovation Centre |
