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Practical considerations in screening for genetic alterations in cholangiocarcinoma

Bekaii-Saab, TS; Bridgewater, J; Normanno, N; (2021) Practical considerations in screening for genetic alterations in cholangiocarcinoma. Annals of Oncology 10.1016/j.annonc.2021.04.012. (In press). Green open access

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Abstract

Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as IDH1 mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and approximately 10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the FGFR1-3 inhibitor pemigatinib, has been approved. However, favorable phase 3 results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the US. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient’s genetic signature.

Type: Article
Title: Practical considerations in screening for genetic alterations in cholangiocarcinoma
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.annonc.2021.04.012
Publisher version: https://doi.org/10.1016/j.annonc.2021.04.012
Language: English
Additional information: This is an Open Access article published under a Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Actionable genetic alterations, cholangiocarcinoma, genomic profiling, next-generation sequencing, targeted therapy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10127262
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