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.

scholarly journals Integrated Analysis of Copy Number Variation, Microsatellite Instability, and Tumor Mutation Burden Identifies an 11-Gene Signature Predicting Survival in Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin Jin ◽  
Junfeng Yan ◽  
Chuanzhi Chen ◽  
Yi Chen ◽  
Wen-Kuan Huang
Keyword(s):  
Breast Cancer ◽  
Copy Number Variation ◽  
Genetic Variants ◽  
Copy Number ◽  
Risk Model ◽  
Gene Signature ◽  
Integrated Analysis ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Number Variation

Genetic variants such as copy number variation (CNV), microsatellite instability (MSI), and tumor mutation burden (TMB) have been reported to associate with the immune microenvironment and prognosis of patients with breast cancer. In this study, we performed an integrated analysis of CNV, MSI, and TMB data obtained from The Cancer Genome Atlas, thereby generating two genetic variants-related subgroups. We characterized the differences between the two subgroups in terms of prognosis, MSI burden, TMB, CNV, mutation landscape, and immune landscape. We found that cluster 2 was marked by a worse prognosis and lower TMB. According to these groupings, we identified 130 differentially expressed genes, which were subjected to univariate and least absolute shrinkage and selection operator-penalized multivariate modeling. Consequently, we constructed an 11-gene signature risk model called the genomic variation-related prognostic risk model (GVRM). Using ROC analysis and a calibration plot, we estimated the prognostic prediction of this GVRM. We confirmed the predictive efficiency of this GVRM by validating it in another independent International Cancer Genome Consortium cohort. Our results conclude that an 11-gene signature developed by integrated analysis of CNV, MSI, and TMB has a high potential to predict breast cancer prognosis, which provided a strong rationale for further investigating molecular mechanisms and guiding clinical decision-making in breast cancer.

The mutational landscape of circulating cell-free DNA to identify neoadjuvant chemotherapy response in colorectal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15096-e15096
Author(s):  
Yanlong Liu ◽  
Xiaoli Wei ◽  
Xinying Shi ◽  
Ying Yang ◽  
Lili Fu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Copy Number Variation ◽  
Cancer Patients ◽  
Candidate Genes ◽  
Copy Number ◽  
Free Dna ◽  
Number Variation ◽  
Colorectal Cancer Patients ◽  
Response To Neoadjuvant Chemotherapy

e15096 Background: The neoadjuvant chemotherapy plays an important role in the current treatment of colorectal cancer (CRC), even though parts of patients could not be benefit from it. This study was aimed to explore the specific mutational profile of plasma cell free DNA (cfDNA) in CRC patients with or without response to neoadjuvant chemotherapy. Methods: 16 eligible CRC patients were enrolled in this study from Harbin Medical University Cancer Hospital. These patients were divided into two groups: with response ( R, n = 8) and without response (NR, n = 8) to neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy and their baseline blood samples were collected. The cfDNA fragments were extracted for enrichment of a panel covering exon regions of 1,086 genes. Gene alterations were analyzed to investigate the relationship between genetic characterizations of cfDNA and response to neoadjuvant chemotherapy. Results: Principal component (PCA) analysis for copy number variation(CNV) of cfDNA differed significantly in two groups. In the R group, there were higher frequency CNV loss in ABL-1, ERBB3, SMO, IGF1R, AURKA, PDGFRA, IDH1, BRAF, PIK3CB, NRAS, NF1, MITF, PTCH1 genes, and CNV gain in MTRR, HSP90AA1, VHL, CREBBP, CHEK2, DDR2, MUTYH, NCOA1, XPC, FANCA genes. Regarding to the area under the ROC curve, CNV of these genes had a high value of 0.967, which implied that CNV of the candidate genes have predictive value for identifying response to neoadjuvant chemotherapy in CRC patients. Furthermore, the Copy Number Instability (CNI) value of R group was significantly higher than NR group(p = 0.0014). Conclusions: The candidate genes’ copy number variation and CNI value of baseline plasma cfDNA can identify the colorectal cancer patients with response or without response to neoadjuvant chemotherapy in this small cohort. The molecular profile of cfDNA in plasma may be a potential biomarker for predicting the response to neoadjuvant chemotherapy in colorectal cancer patients. These findings warrant further expanded prospective cohorts to validate.

scholarly journals The effect of copy number variation in the phase II detoxification genesUGT2B17andUGT2B28on colorectal cancer risk

Cancer ◽  
2013 ◽  
Vol 119 (13) ◽  
pp. 2477-2485 ◽  
Author(s):  
Andrea Y. Angstadt ◽  
Arthur Berg ◽  
Junjia Zhu ◽  
Paige Miller ◽  
Terryl J. Hartman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Copy Number Variation ◽  
Phase Ii ◽  
Copy Number ◽  
Colorectal Cancer Risk ◽  
Number Variation

scholarly journals Characteristics of Pan-Cancer Patients With Ultrahigh Tumor Mutation Burden

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong Yuan ◽  
Jun Ji ◽  
Min Shi ◽  
Yan Shi ◽  
Jing Liu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Microsatellite Instability ◽  
Dna Damage Repair ◽  
Oncogenic Signaling ◽  
Tumor Mutation Burden ◽  
Dna Mismatch ◽  
Damage Repair ◽  
Mutation Burden ◽  
Number Variation ◽  
Group A

BackgroundTumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients.MethodsA total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed.ResultsAmong the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different.ConclusionsThis study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

Analysis of TGCA data reveals genetic and epigenetic changes and biological function of MUC family genes in colorectal cancer

2019 ◽  
Vol 15 (35) ◽  
pp. 4031-4043 ◽  
Author(s):  
Zhipeng Jiang ◽  
Huashe Wang ◽  
Liang Li ◽  
Zehui Hou ◽  
Wei Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number Variation ◽  
Copy Number ◽  
Regulatory Networks ◽  
The Cancer Genome Atlas ◽  
Epigenetic Changes ◽  
Copy Number Variation Analysis ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Drug Influence

Aim: Few studies focused on functions and regulatory networks of MUC family members in colorectal cancer based on comprehensive analysis of online database. Materials & methods: Copy number variation, methylation, pathway analysis and drug influence on MUC expression were analyzed based on The Cancer Genome Atlas and GTEx database. Results: Copy number variation analysis showed MUC heterozygous amplification and heterozygous deletion predominate. Methylation of MUC17, MUC12 and MUC4 were found related to gene expression. Function of MUC family genes mainly affects pathways such as apoptosis, cell cycle, DNA damage and EMT pathways. PLX4720, dabrafenib, gefitinib, afatinib and austocystin D can alter the expression of MUC gene. Conclusion: The genetic and epigenetic changes of MUC are related to the level of MUC expression in colorectal cancer.

NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3544-3544
Author(s):  
Hui WANG ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
Misako Nagasaka ◽  
Sai-Hong Ignatius Ou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Neurotrophin Receptor ◽  
Driver Mutations ◽  
Fusion Partner ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
Colorectal Cancer Patients

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( < 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

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