Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice

Xue, Lijun; Guo, Chao; Zhang, Kang; Jiang, Hang; Pang, Fei; Dou, Ying; Liu, Xiaoyan; Lin, Hanqing; Dong, Xiaowei; Zhao, Shuaiguo; Yao, Ming; Wang, Kai; Feng, Yujie; Gu, Weiguang

doi:10.21037/hbsn.2019.08.05

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…A number of recent studies have used comprehensive genomic profiling to determine the frequency of different genomic alterations in patients with CCA, including those with prior histopathologic diagnosis of iCCA versus eCCA. 17,[22][23][24][25][26][27][28] Although these studies varied with respect to the numbers of genes and patients analyzed, the overall findings suggest substantial heterogeneity among the molecular profiles of individual patients and important differences between the molecular landscapes of iCCA and eCCA (Figure 1). In the largest study reported to date, Javle et al profiled tumor samples from 4371 patients with CCA to identify alterations in exons and select introns of up to 404 genes and to determine tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity.…”

Section: Frequently Altered Genesmentioning

confidence: 99%

“…23 Of note, a particularly high rate of TP53 alterations (68%) was found in 80 Chinese patients with eCCA (Figure 1C). 26 Along with the apparent differences in molecular landscapes between CCA subtypes, the molecular profile of CCA is also geographically heterogeneous, which may reflect divergent extrinsic risk factors and etiologies. 6 In this regard, a recent next-generation sequencing (NGS) study compared genomic profiles of patients with iCCA located in the United States (n ¼ 283) with those in China (n ¼ 164).…”

Section: Frequently Altered Genesmentioning

confidence: 99%

“…30 Also, consistent with this, a particularly high rate of TP53 alterations was observed in 80 Chinese patients with eCCA (Figure 1C). 26 Notably, an integrative clustering analysis of copy number, gene expression, mutation, and epigenetic data from 489 CCA samples spanning 10 countries yielded four clusters characterized by divergent clinicopathologic and molecular PaƟents (%) In two of the studies listed in A, Silverman et al 2021 25 profiles. 13 Clusters 1 and 2 primarily encompassed liver fluke-positive CCAs and were enriched in ERBB2 amplification and TP53 mutation; clusters 3 and 4 primarily encompassed liver fluke-negative CCAs, with cluster 3 displaying immune checkpoint gene up-regulation (PD1, PD-L1, and BTLA), and cluster 4 exhibiting IDH1/2 and BAP1 mutations, as well as FGFR alterations.…”

Section: Frequently Altered Genesmentioning

confidence: 99%

“…25 Quantitative data for actionable genetic alterations in patients with eCCA are limited, due to the small number of studies specifically conducted in this patient population, relatively small sample sizes, and variable criteria used to identify actionable genetic alterations. 15,23,26 Important differences between the molecular profiles of eCCA and iCCA are the low frequency of IDH1 mutations and apparent lack of FGFR2 fusions/rearrangements in eCCA. 15,23,24,26 Results of a recent study in 189 patients with eCCA suggest that w25% of the patients harbor actionable mutations.…”

Section: Clinically Actionable Genetic Alterationsmentioning

confidence: 99%

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Practical considerations in screening for genetic alterations in cholangiocarcinoma

2021

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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 isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and w10% 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 fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III 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 United States. 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.

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Section: Frequently Altered Genesmentioning

confidence: 99%

Section: Frequently Altered Genesmentioning

confidence: 99%

Section: Frequently Altered Genesmentioning

confidence: 99%

Section: Clinically Actionable Genetic Alterationsmentioning

confidence: 99%

See 2 more Smart Citations

Practical considerations in screening for genetic alterations in cholangiocarcinoma

2021

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“…In a cohort of 80 Chinese patients with eCCA, Xue et al (33) reported that the most frequently altered genes were TP53 (68%), followed by KRAS (46%), SMAD4 (22%), ARID1A (20%), and CDKN2A (19%). The top three actionable alterations included CDKN2A (n = 11), BRAF (n = 5), and ERBB2 (n = 4).…”

Section: Molecular Targeted Therapymentioning

confidence: 99%

Systemic treatment of advanced or recurrent biliary tract cancer

Zhang

Zhou

Wang

et al. 2020

BST

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Immune checkpoint inhibitor‐related molecular markers predict prognosis in extrahepatic cholangiocarcinoma

Jin,

Wang,

Zhang

et al. 2023

Cancer Medicine

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BackgroundTherapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications.MethodsWhole‐exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI).ResultsMutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056–0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36.ConclusionsTMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

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Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice

Cited by 16 publications

References 31 publications

Practical considerations in screening for genetic alterations in cholangiocarcinoma

Practical considerations in screening for genetic alterations in cholangiocarcinoma

Systemic treatment of advanced or recurrent biliary tract cancer

Immune checkpoint inhibitor‐related molecular markers predict prognosis in extrahepatic cholangiocarcinoma

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