scholarly journals Clinically Significant Shared and Distinct Genomic Alterations in Chinese and Western Patients with Intrahepatic Cholangiocarcinoma

2020 ◽  
Author(s):  
Shifeng Xu ◽  
Yuan Guo ◽  
Yanwu Zeng ◽  
Zhijian Song ◽  
Xiaodan Zhu ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Chinese Patients ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Public Dataset ◽  
Clinically Significant ◽  
Two Populations

Abstract Background The goal of this study is to disclose the clinically significant genomic alterations in patients with intrahepatic cholangiocarcinoma of the Chinese and Western populations.Methods A total of 86 Chinese patients were enrolled in this study. Samples from those patients were sequenced for a panel of pan-cancer genes. Results were compared to a public dataset from a cohort of Western patients. The comparison between the two populations was conducted in the driver genes, actionability, and TMB.Results The Chinese and Western cohorts had 38 and 12 driver genes, respectively. Seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. For both cohorts, half of the patients had actionable mutations. The two cohorts shared most of the actionable genes but differed much in the frequency. Though KRAS mutations were at the first and second actionable rank respectively for Chinese and Western populations, they were still at a relatively low level of actionable evidence. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutation burden.Conclusions The revealed genomic alterations with clinical significance could help to improve the treatment of intrahepatic cholangiocarcinoma.

scholarly journals Clinically significant shared and distinct genomic alterations in Chinese and Western patients with intrahepatic cholangiocarcinoma

2020 ◽  
Author(s):  
Shifeng Xu ◽  
Yuan Guo ◽  
Yanwu Zeng ◽  
Zhijian Song ◽  
Xiaodan Zhu ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Chinese Patients ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Kras Mutations ◽  
Public Dataset ◽  
Clinically Significant ◽  
Two Populations ◽  
Pan Cancer

Abstract BackgroundThe goal of this study is to disclose the clinically significant genomic alterations in patients with intrahepatic cholangiocarcinoma of the Chinese and Western populations.MethodsA total of 86 Chinese patients were enrolled in this study. Samples from those patients were sequenced for a panel of pan-cancer genes. Results were compared to a public dataset from a cohort of Western patients. The comparison between the two populations was conducted in the driver genes, actionability, and tumor mutational burden.ResultsThe Chinese and Western cohorts had 36 and 12 driver genes, respectively. Seven driver genes ( IDH1 , KRAS , TP53 , BAP1 , PBRM1 , ARID1A, and NRAS ) were shared by the two cohorts. For both cohorts, half of the patients had actionable mutations. The two cohorts shared most of the actionable genes but differed much in the frequency. Though KRAS mutations were at the first and second actionable rank respectively for Chinese and Western populations, they were still at a relatively low level of actionable evidence. Four driver genes ( SPTA1 , ARID2 , TP53 , and GATA1 ) were found significantly correlated with the tumor mutational burden.ConclusionsThe revealed genomic alterations with clinical significance could help to improve the treatment of intrahepatic cholangiocarcinoma.

scholarly journals Clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shifeng Xu ◽  
Yuan Guo ◽  
Yanwu Zeng ◽  
Zhijian Song ◽  
Xiaodan Zhu ◽  
...  
Keyword(s):  
Future Development ◽  
Intrahepatic Cholangiocarcinoma ◽  
Chinese Patients ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Clinically Significant ◽  
Pan Cancer

Abstract Background The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. Methods A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. Results Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. Conclusions The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

scholarly journals Comprehensive analysis of genomic mutation signature and tumor mutation burden for prognosis of intrahepatic cholangiocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Zhang ◽  
Qi Li ◽  
Jialu Fu ◽  
Zhechuan Jin ◽  
Jingbo Su ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Cox Regression ◽  
Tnm Stage ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Tumor Mutation Burden ◽  
Kaplan Meier ◽  
Mutation Burden ◽  
Significant Difference ◽  
Genomic Mutation

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy of the biliary tract. Analysis of somatic mutational profiling can reveal new prognostic markers and actionable treatment targets. In this study, we explored the utility of genomic mutation signature and tumor mutation burden (TMB) in predicting prognosis in iCCA patients. Methods Whole-exome sequencing and corresponding clinical data were collected from the ICGC portal and cBioPortal database to detect the prognostic mutated genes and determine TMB values. To identify the hub prognostic mutant signature, we used Cox regression and Lasso feature selection. Mutation-related signature (MRS) was constructed using multivariate Cox regression. The predictive performances of MRS and TMB were assessed using Kaplan–Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis using gene set enrichment analysis (GSEA) for mutated genes. Based on the MRS, TMB, and the TNM stage, a nomogram was constructed to visualize prognosis in iCCA patients. Results The mutation landscape illustrated distributions of mutation frequencies and types in iCCA, and generated a list of most frequently mutated genes (such as Tp53, KRAS, ARID1A, and IDH1). Thirty-two mutated genes associated with overall survival (OS) were identified in iCCA patients. We obtained a six-gene signature using the Lasso and Cox method. AUCs for the MRS in the prediction of 1-, 3-, and 5-year OS were 0.759, 0.732, and 0.728, respectively. Kaplan–Meier analysis showed a significant difference in prognosis for patients with iCCA having a high and low MRS score (P < 0.001). GSEA was used to show that several signaling pathways, including MAPK, PI3K-AKT, and proteoglycan, were involved in cancer. Conversely, survival analysis indicated that TMB was significantly associated with prognosis. GSEA indicated that samples with high MRS or TMB also showed an upregulated expression of pathways involved in tumor signaling and the immune response. Finally, the predictive nomogram (that included MRS, TMB, and the TNM stage) demonstrated satisfactory performance in predicting survival in patients with iCCA. Conclusions Mutation-related signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for determining outcomes in patients with iCCA.

scholarly journals Cancer-specific associations of driver genes with immunotherapy outcome

2020 ◽  
Author(s):  
Tomi Jun ◽  
Tao Qing ◽  
Guanlan Dong ◽  
Maxim Signaevski ◽  
Julia F Hopkins ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Gene Mutations ◽  
Driver Gene ◽  
Oncogenic Signaling ◽  
Multiple Cancer ◽  
Driver Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Types ◽  
Oncogenic Signaling Pathways

AbstractGenomic features such as microsatellite instability (MSI) and tumor mutation burden (TMB) are predictive of immune checkpoint inhibitor (ICI) response. However, they do not account for the functional effects of specific driver gene mutations, which may alter the immune microenvironment and influence immunotherapy outcomes. By analyzing a multi-cancer cohort of 1,525 ICI-treated patients, we identified 12 driver genes in 6 cancer types associated with treatment outcomes, including genes involved in oncogenic signaling pathways (NOTCH, WNT, FGFR) and chromatin remodeling. Mutations of PIK3CA, PBRM1, SMARCA4, and KMT2D were associated with worse outcomes across multiple cancer types. In comparison, genes showing cancer-specific associations—such as KEAP1, BRAF, and RNF43—harbored distinct variant types and variants, some of which were individually associated with outcomes. In colorectal cancer, a common RNF43 indel was a putative neoantigen associated with higher immune infiltration and favorable ICI outcomes. Finally, we showed that selected mutations were associated with PD-L1 status and could further stratify patient outcomes beyond MSI or TMB, highlighting their potential as biomarkers for immunotherapy.

The landscape of POLE/POLD1 mutations in Chinese solid tumor patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13050-e13050 ◽  
Author(s):  
Linrong Pang ◽  
Tao Xu ◽  
Hua Tao ◽  
Gang Chen ◽  
Bin Ni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endometrial Cancer ◽  
Solid Tumors ◽  
Urothelial Cancer ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Chinese Patients ◽  
Unknown Primary ◽  
Cancer Genes ◽  
Genomic Alterations

e13050 Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p < 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.

PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15267-e15267
Author(s):  
Haihua Yang ◽  
Longgang Cui ◽  
Yuzi Zhang ◽  
Zhengyi Zhao ◽  
Yuezong Bai ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Expression Profiles ◽  
Chinese Patients ◽  
Cancer Type ◽  
Tissue Samples ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

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