High tumor mutation burden indicates a poor prognosis in patients with intrahepatic cholangiocarcinoma

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.

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Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16650 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16650-e16650

Author(s):

Lingling Guo ◽

Xiaoxia Kou ◽

Panpan Song ◽

Xiaoyu Zhang ◽

Hongjuan Zhang ◽

...

Keyword(s):

Biliary Tract ◽

Poor Prognosis ◽

Clinical Decision Making ◽

Clinical Decision ◽

Biliary Tract Carcinoma ◽

Rank Test ◽

Braf Mutations ◽

Tumor Mutation Burden ◽

Synonymous Mutations ◽

Mutation Burden

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.

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PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies

Aging ◽

10.18632/aging.102701 ◽

2020 ◽

Vol 12 (2) ◽

pp. 1577-1590

Author(s):

Yu Tang ◽

Jing Li ◽

Ning Xie ◽

Xiaohong Yang ◽

Liping Liu ◽

...

Keyword(s):

Poor Prognosis ◽

Gene Mutations ◽

Metastatic Breast ◽

Breast Carcinomas ◽

Tumor Mutation Burden ◽

Pik3ca Gene ◽

Helical Domain ◽

Mutation Burden

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Papillary thyroid carcinoma with a high tumor mutation burden has a poor prognosis

International Immunopharmacology ◽

10.1016/j.intimp.2020.107090 ◽

2020 ◽

Vol 89 ◽

pp. 107090

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yu Lun ◽

Yuzhen He ◽

Song Wu ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Poor Prognosis ◽

Papillary Thyroid ◽

Tumor Mutation Burden ◽

Mutation Burden

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

10.21203/rs.3.rs-25576/v1 ◽

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.

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CDC20 is a Potential Prognostic and Immunological Biomarker in Pan-Cancer

10.21203/rs.3.rs-917402/v1 ◽

2021 ◽

Author(s):

Chen Tao ◽

Hu Bing ◽

Zhan Xiangpeng ◽

Liu Xiaoqiang ◽

Deng Wen ◽

...

Keyword(s):

Poor Prognosis ◽

Cell Cycle Progression ◽

Vital Role ◽

Pathological Stage ◽

Cycle Progression ◽

Tumor Mutation Burden ◽

Normal Tissues ◽

Mutation Burden ◽

Immune Related Genes ◽

Pan Cancer

Abstract BackgroundCDC20(cell division cycle 20 homologue) plays a vital role in the cell cycle progression through targeting key substrates for destruction. Current studies have shown that CDC20 functions as an oncogene in various cancers. However, the potential correlations of CDC20 with prognosis and immune infiltrates in different cancers remain unclear.ResultCDC20 expression was higher in most cancers, compared with normal tissues, and the high expression of CDC20 was correlated with poor prognosis and a higher pathological stage. Furthermore, there were significant correlations between CDC20 dysregulation with tumor mutation burden(TMB), microsatellite instability(MSI), tumor microenvironment and tumor- and immune-related genes.ConclusionCDC20 may be used as a potential prognostic and immunotherapeuticbiomarker which affects tumor progression.

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Comprehensive Analysis of Genomic Mutation Signature and Tumor Mutation Burden for Prognosis of Intrahepatic Cholangiocarcinoma

10.21203/rs.3.rs-89482/v1 ◽

2020 ◽

Author(s):

Rui Zhang ◽

Qi Li ◽

Jialu Fu ◽

Zhechuan Jin ◽

Jingbo Su ◽

...

Keyword(s):

Signaling Pathways ◽

Signaling Pathway ◽

Intrahepatic Cholangiocarcinoma ◽

Cox Regression ◽

Tnm Stage ◽

Gene Set Enrichment Analysis ◽

Tumor Mutation Burden ◽

Kaplan Meier ◽

Mutation Burden ◽

Genomic Mutation

Abstract Background: The intrahepatic cholangiocarcinoma (iCCA) is highly lethal malignancy of biliary tract cancer. Analysis of somatic mutational profiling could help to reveal new prognostic markers and actionable targets for treatment. We aim to explore the impact of genomic mutation signature and tumor mutation burden (TMB) on prognosis of iCCA patients. Methods: The whole-exome sequencing and corresponding clinical data were collected from ICGC portal and cBioPortal database to detect the mutation prognostic genes and TMB values. To identify the hub prognostic mutant signature, Cox regression and Lasso feature selection were conducted. We built a mutation related signature (MRS) through multivariate Cox regression. The predictive performance of MRS and TMB were assessed using Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis with gene set enrichment analysis (GSEA) for mutated genes were conducted. Moreover, on the base of MRS, TMB and TNM stage, a nomogram was constructed to visualize the prognosis of iCCA patients.Results: The mutation landscape illustrated the distributions of mutation frequencies and types on iCCA, and revealed a list of most frequent mutation genes (such as Tp53, KRAS, ARID1A, IDH1). We obtain a 6- gene signature using the Lasso and Cox method. The AUC of MRS in 1, 3, 5-year OS prediction were 0.759, 0.732, 0.728, respectively. Moreover, Kaplan-Meier analysis showed a significant difference on the prognosis of iCCA with high and low MRS score (P <0.001). Interestingly, GSEA was utilized to show several signaling pathways including MAPK signaling pathway, PI3K-AKT signaling pathway and proteoglycans in cancer. On the other hand, survival analysis indicated that TMB was significantly associated with prognosis. And GSEA indicated that samples with high MRS or TMB upregulated signaling pathways involved in tumor signaling and immune system. At last, we constructed a predictive nomogram (included MRS, TMB and TNM stage) with satisfactory performance in survival prediction. Conclusions: The mutation genes signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for further uncovering molecular pathogenesis in iCCA.

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FAT3 Mutation Is Associated With Tumor Mutation Burden and Poor Prognosis in Esophageal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.603660 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zixin Guo ◽

Xin Yan ◽

Congkuan Song ◽

Qingwen Wang ◽

Yujin Wang ◽

...

Keyword(s):

Esophageal Cancer ◽

Prognostic Marker ◽

Somatic Mutation ◽

Poor Prognosis ◽

Potential Mechanism ◽

Wild Type ◽

Mutant Type ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Mutation Type

ObjectiveTo explore the mutated genes in esophageal cancer (ESCA), and evaluate its relationship with tumor mutation burden (TMB) and prognosis of ESCA, and analyze the advantages of FAT3 as a potential prognostic marker in ESCA.MethodsThe somatic mutation landscape was analyzed according to ESCA samples from the TCGA and ICGC database. The differences of TMB between mutant type and wild type of frequently mutated genes were compared by Mann-Whitney U test. The association of gene mutations with prognosis was analyzed by Kaplan-Meier method. The relative abundance of 22 tumor-infiltrating lymphocyte subsets in ESCA was calculated by CIBERSORT algorithm.ResultsFAT3 was a high frequency mutation in both TCGA and ICGC samples from the somatic mutation landscape. Then, the mutation type of FAT3 had significantly higher TMB in patients with ESCA compared the wild type (P<0.05). Meanwhile, the prognosis of FAT3 mutation type was significantly worse in patients with ESCA(P<0.05), and the FAT3 mutation status might be an independent factor for prognosis of patients with ESCA (HR: 1.262–5.922, P=0.011). The GSEA analysis revealed the potential mechanism of FAT3 mutation on the occurrence and development of ESCA. Finally, naive B cells were significantly enriched in FAT3 mutation samples of the ESCA microenvironment (P<0.05).ConclusionsFAT3 mutation is related to TMB and poor prognosis in ESCA. FAT3 mutation may be a prognostic marker of ESCA, and reveal the potential mechanism of FAT3 mutation on ESCA.

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