scholarly journals Identification of Tumor Mutation Burden, Microsatellite Instability, and Somatic Copy Number Alteration derived 9-gene Signatures to Predict Clinical Outcomes in STAD

2021 ◽  
Author(s):  
Chuanzhi Chen ◽  
Yi Chen ◽  
Xin Jin ◽  
Yongfeng Ding ◽  
Junjie Jiang ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Copy Number ◽  
Copy Number Alteration ◽  
External Validation ◽  
The Cancer Genome Atlas ◽  
Roc Curve Analysis ◽  
Predictive Tool ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Somatic Copy Number Alteration

Abstract Background: Genomic features including tumor mutation burden (TMB), microsatellite instability (MSI) and somatic copy number alteration (SCNA), had been demonstrated to be involved with the tumor microenvironment (TME) and outcome of gastric cancer (GC). Methods: We obtained profiles of TMB, MSI and SCNA by processing 405 GC data from The Cancer Genome Atlas (TCGA), then conducted a comprehensive analysis though “iClusterPlus”. Another independent Gene Expression Omnibus (GEO) contained specimens from 109 GC patients was designed as an external validation. Results: Two subgroups were generated, with distinguished prognosis, somatic mutation burden, copy number changes and immune landscape. We revealed that Cluster1 was marked by a better prognosis, accompanied by higher TMB, MSIsensor score, TMEscore, and lower SCNA burden. Based on these clusters, we screened 196 differentially expressed genes (DEGs), which were subsequently projected into univariate Cox survival analysis. Thus, we constructed a 9-gene immune risk score (IRS) model using lasso penalized logistic regression. Moreover, the prognostic prediction of IRS was verified by receiver operating characteristic (ROC) curve analysis and nomogram plot.Conclusions: Our works suggested that the 9‐gene‐signature prediction model, which derived from TMB, MSI, SCNA was a promising predictive tool for clinical outcome in GC patients. This novel methodology may help clinicians uncover the underlying mechanisms and guide future treatment strategies.

The mutational landscape of MSI-H and MSS colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15122-e15122
Author(s):  
Enxiao LI ◽  
Ying Hu ◽  
Wenbo Han ◽  
Tianshu Liu ◽  
Fang Lv ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number Variation ◽  
Microsatellite Instability ◽  
Copy Number ◽  
Mononucleotide Repeat ◽  
Tumor Mutation Burden ◽  
Mutational Landscape ◽  
Mutation Burden ◽  
Keywords Colorectal Cancer ◽  
Number Variation

e15122 Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

scholarly journals The landscape of somatic copy-number alteration across human cancers

Nature ◽  
2010 ◽  
Vol 463 (7283) ◽  
pp. 899-905 ◽  
Author(s):  
Rameen Beroukhim ◽  
Craig H. Mermel ◽  
Dale Porter ◽  
Guo Wei ◽  
Soumya Raychaudhuri ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Human Cancers ◽  
Somatic Copy Number Alteration

Comprehensive genomic sequencing of high-grade neuroendocrine neoplasms.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 624-624
Author(s):  
Thomas Yang Sun ◽  
Paul Van Hummelen ◽  
Brock Martin ◽  
Charlie Xia ◽  
Hojoon Lee ◽  
...  
Keyword(s):  
Copy Number ◽  
Cox Model ◽  
Predictive Biomarkers ◽  
Neuroendocrine Neoplasms ◽  
Tumor Mutation Burden ◽  
Risk Of Death ◽  
Mutation Burden ◽  
Increased Risk ◽  
Poorly Differentiated ◽  
Copy Number Changes

624 Background: Grade 3 neuroendocrine neoplasms (G3 NENs), if poorly differentiated, have a median survival of only 10-19 months. Little is known regarding their underlying genomics. Methods: We applied multiomics analysis to 46 cases of G3 NEN that included copy number analysis, whole exome, and transcriptomic sequencing. Results: Of the 46 unique cases, 17 were lung, 16 gastroenteropancreatic (GEP), 13 other; 5 well-differentiated, 39 poorly differentiated and 2 mixed. Using a multivariate Cox model, we found histology characteristics (including differentiation, Ki67 and mitotic index) did not correlate with changes in overall survival (OS). The clinical variables that did correlate with OS included: number of lines of treatment (hazard ratio for death [HR], 0.72; p < 0.05), GEP primary site (HR, 5.36; p < 0.005), and non-resected primary tumor (HR, 14.52; p < 0.001). Two copy number changes were associated with worse prognosis: focal deletion 22q13 (HR, 10.23; p < 0.005), and arm amplification 19q (HR, 7.09; p < 0.01). The median OS of the top quartile compared to the rest for 22q13 deletion carriers was 9.9 months vs. 24 months, and for 19q amplification carriers was 8.7 months vs. 36.7 months. We estimated a median tumor mutation burden (TMB) of 3.7 mutations/Mb, with 20% (8/40) of patients showing high TMB ( > 10 mutations/Mb). The top five mutated genes were USH2A, RB1, APC, TP53, and MUC16. We also observed high transcriptomic similarity across all NENs regardless of their site of origin. Conclusions: We identified two copy number changes that can serve as predictive biomarkers in G3 NENs, as they confer an increased risk of death by as high as 10x to the carriers. Further, G3 NENs are characterized by a distinct group of somatic mutations, and a significant number have high tumor mutation burden. Lastly, G3 NENs across different organs were relatively homogeneous in expression profile.

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