Association of driver genes with high-tumor mutation burden and outcome in patients with head and neck cancer: Implications for immunotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18533-e18533
Author(s):  
Yu Chen ◽  
Chuan-ben Chen ◽  
Xiao-bin Zheng ◽  
Xuan Gao ◽  
Liu Jun ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Peripheral Blood Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Driver Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Chinese Cohort

e18533 Background: While the immune checkpoint blockades had demonstrated promising benefits in head and neck cancer (HNSC), its clinical efficacy is limited to a selected subset of less than 20% HNSC patients. Tumor mutation burden (TMB) has been reported as a predictor for ICBs in multiple tumors, including HNSC. However, the association of driver genes with TMB and outcomes in patients with HNSC has not yet been established. Methods: Somatic mutation landscape was characterized by interactively analyzed the sequencing data of 495 HNSC samples obtained from The Cancer Genome Atlas (TCGA) database and 185 samples from a Chinese cohort (Geneplus-database). Hybrid capture of a 1021 gene panel with potential clinical relevance was performed on tumor and paired Peripheral blood lymphocytes (PBLs) from 185 HNSC samples in a Chinese cohort. Results: In the Chinese cohort, patients harboring ≥5 muts/Mb (the top quartile of tTMB distribution) were classified as the TMB-H group; while ≥4.7 muts/Mb were classified as the TMB-M group. TMB -H was associated with better OS in the TCGA cohort. The rest were classified as TMB-L patients. Thirteen aberrant genes were significant correlation with TMB-H, including TSC2, POLE, CDK4, TSC1, MLH1, PTCH1, NF1, MSH3, RAD50, MSH2, CDH1, TNFRSF14, TERC. Among them,10 were further verified in the TCGA Head and Neck Cancer cohort, including TNFRSF14, MSH3, NF1, TSC2, RAD50, MSH2, PTCH1, POLE, MLH1, TSC1. Moreover, aberrant genes such as CDH1, MSH2 and RAD50 implicated better DFS (DFS:HR = .296, p = .034; HR = 0.128, p = .016; HR = .0422, p = .043) in HNSC of the TCGA cohort. Transcriptomic analysis in the TCGA Head and Neck Cancer cohort showed various degrees of immune upregulation in the tumor microenvironment (TME) in CDH1, MSH2, and RAD50 mutated population. Conclusions: These findings indicated that CDH1, MSH2, and RAD50 mutations may be associated with TMB-H, immuno-upregulation in TME and better survival outcomes. Combined with TMB, genes mentioned above may give us some insights into how ICB therapeutic strategies assist natural host immune responses against HNSC in Chinese population.

scholarly journals Decomposing the subclonal structure of tumors with two-way mixture models on copy number aberrations

2018 ◽  
Author(s):  
An-Shun Tai ◽  
Chien-Hua Peng ◽  
Shih-Chi Peng ◽  
Wen-Ping Hsieh
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Tumor Evolution ◽  
Depth Information ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Copy Number Aberrations

AbstractMultistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs.

scholarly journals 3p Arm Loss and Survival in Head and Neck Cancer: An Analysis of TCGA Dataset

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5313
Author(s):  
Hugh Andrew Jinwook Kim ◽  
Mushfiq Hassan Shaikh ◽  
Mark Lee ◽  
Peter Y. F. Zeng ◽  
Alana Sorgini ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Survival Data ◽  
Statistical Power ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Cytokine Signaling ◽  
Molecular Characteristics ◽  
Chromosome 3P

Loss of the 3p chromosome arm has previously been reported to be a biomarker of poorer outcome in both human papillomavirus (HPV)-positive and HPV-negative head and neck cancer. However, the precise operational measurement of 3p arm loss is unclear and the mutational profile associated with the event has not been thoroughly characterized. We downloaded the clinical, single nucleotide variation (SNV), copy number aberration (CNA), RNA sequencing, and reverse phase protein assay (RPPA) data from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas HNSCC cohorts. Survival data and hypoxia scores were downloaded from published studies. In addition, we report the inclusion of an independent Memorial Sloan Kettering cohort. We assessed the frequency of loci deletions across the 3p arm separately in HPV-positive and -negative disease. We found that deletions on chromosome 3p were almost exclusively an all or none event in the HPV-negative cohort; patients either had <1% or >97% of the arm deleted. 3p arm loss, defined as >97% deletion in HPV-positive patients and >50% in HPV-negative patients, had no impact on survival (p > 0.05). However, HPV-negative tumors with 3p arm loss presented at a higher N-category and overall stage and developed more distant metastases (p < 0.05). They were enriched for SNVs in TP53, and depleted for point mutations in CASP8, HRAS, HLA-A, HUWE1, HLA-B, and COL22A1 (false discovery rate, FDR < 0.05). 3p arm loss was associated with CNAs across the whole genome (FDR < 0.1), and pathway analysis revealed low lymphoid–non-lymphoid cell interactions and cytokine signaling (FDR < 0.1). In the tumor microenvironment, 3p arm lost tumors had low immune cell infiltration (FDR < 0.1) and elevated hypoxia (FDR < 0.1). 3p arm lost tumors had lower abundance of proteins phospho-HER3 and ANXA1, and higher abundance of miRNAs hsa-miR-548k and hsa-miR-421, which were all associated with survival. There were no molecular differences by 3p arm status in HPV-positive patients, at least at our statistical power level. 3p arm loss is largely an all or none phenomenon in HPV-negative disease and does not predict poorer survival from the time of diagnosis in TCGA cohort. However, it produces tumors with distinct molecular characteristics and may represent a clinically useful biomarker to guide treatment decisions for HPV-negative patients.

scholarly journals Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

PLoS Medicine ◽  
2015 ◽  
Vol 12 (2) ◽  
pp. e1001786 ◽  
Author(s):  
Edmund A. Mroz ◽  
Aaron M. Tward ◽  
Rebecca J. Hammon ◽  
Yin Ren ◽  
James W. Rocco
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Genetic Heterogeneity ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Neoantigen-based vaccination as a practical measure for head and neck cancer treatment.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18528-e18528
Author(s):  
Xiao-bin Zheng ◽  
Chuan-ben Chen ◽  
Yu Chen ◽  
Shiguang Hao ◽  
Liu Jun ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Cancer Treatment ◽  
Head And Neck ◽  
Neck Cancer ◽  
Hla Typing ◽  
Sequencing Data ◽  
Coding Regions ◽  
Standard Procedures ◽  
Potential Vaccine ◽  
Practical Measure

e18528 Background: The view that neoantigens serve as potential vaccine targets has arisen in the last decade. Clinical and computational efforts have been done to increase the practicality of its application in real world. With these advances, we conducted a retrospective study on a Chinese population to explore the clinical feasibility of neoantigen-based vaccines for head and neck cancer treatment. Methods: Tumor and normal samples were profiled using a 1021-gene panel. Sequencing data were pre-analyzed according to our in-house standard procedures. Class I HLA typing was completed using OptiType v1.0. Curated somatic mutations in coding regions (SNVs and non-frameshift Indels with an allele frequency ≥ 5%) were collected and altered peptides produced by these mutations were analyzed using NetMHCpan v4.0. Peptides with an IC50 < 500 nM were considered potential binders, and especially, those with an IC50 < 50 nM were considered strong binders. An altered peptide was considered a neoantigen if IC50 altered is < IC50 wildtype. Results: We analyzed a total of 243 patients and detected 114 unique HLA alleles. By carrier percentage, the top three alleles are C*01:02 (44%), B*46:01 (36%), and A*11:01 (33%). In total, 743 mutations were deemed eligible for neoantigen prediction and 223 unique neoantigens were found. Of these neoantigens, 67 (carried by 21% of patients) were strong binders, among which 26 (carried by 9% patients) exhibited a great fold change (≥ 5 folds) of binding affinity. Moreover, the neoantigens in these patients are unique, as only two neoantigens were shared. A search for shared neoantigens revealed a combination of mutation PIK3CA p.E542K and HLA A*11:01, which was detected in 0.54% of all patients. Additionally, 43.6% (106/243) of patients were diagnosed with nasopharyngeal carcinoma, among whom 42% (44/106) possessed predicted neoantigens, including 15 patients with strong-binder neoantigens. Conclusions: (1) Neoantigen-based vaccination is a practical measure to treat patients with head and neck cancer, as indicated by the percentage of patients harboring strong-binder neoantigens. (2) Off-the-shelf neoantigen vaccines may not be practical, given the result that the most common combination of a neoantigen-producing mutation and the corresponding HLA was only found in 0.54% of all patients.

scholarly journals Amifostine Modulates Radio-induced Apoptosis of Peripheral Blood Lymphocytes in Head and Neck Cancer Patients

2010 ◽  
Vol 51 (5) ◽  
pp. 603-607 ◽  
Author(s):  
Maite M. SAAVEDRA ◽  
Luis Alberto HENRÍQUEZ-HERNÁNDEZ ◽  
Pedro C. LARA ◽  
Beatriz PINAR ◽  
Carlos RODRÍGUEZ-GALLEGO ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cancer Patients ◽  
Neck Cancer ◽  
Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
Blood Lymphocytes ◽  
Induced Apoptosis

scholarly journals The kinetics of γ-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis

2020 ◽  
Vol 54 (1) ◽  
pp. 96-102
Author(s):  
Joanna Kazmierska ◽  
Wojciech Barczak ◽  
Tomasz Winiecki ◽  
Łukasz Łuczewski ◽  
Magdalena Marciniak ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Peripheral Blood Lymphocytes ◽  
Significant Difference ◽  
Radiation Induced ◽  
The Difference ◽  
Kinetics Of ◽  
Severe Mucositis

AbstractBackgroundThe aim of the study was to evaluate the changes in γ-H2AX expression in peripheral blood lymphocytes (PBL) according to severity of radiation-induced mucositis.Patients and methodFifty patients with head and neck cancer treated with radiotherapy (RT) or chemoradiation were included in the study. Blood samples were collected before treatment to measure baseline γ-H2AX levels. Second sample was taken 45 minutes after the first RT fraction and then once a week, 45 min after irradiation. In patients treated with chemoradiation the blood sample was taken the day after chemotherapy. Mucositis was evaluated once a week and reported according to CTCAE v4 and RTOG/EORTC scales. PBL were analyzed with flow cytometry and level of H2AX phosphorylation at every time point was evaluated.ResultsIn 35 patients mild to moderate (grade 1–2) mucositis was observed and 15 patients developed severe (grade 3) mucositis. No cases of grade 4 mucositis were observed. The difference in baseline levels of γ-H2AX between groups with mild and severe mucositis was statistically insignificant (p = 0.25). The statistically significant difference in γ-H2AX level was observed in week 7 of treatment (p = 0.01). No significant differences in γ-H2AX level were found neither between group treated with concomitant chemoradiation or RT alone neither between groups with and without common comorbidities. In the analysis of the kinetics of γ-H2AX during treatment, a statistically significant difference (p = 0.0088) between groups with mild and severe mucositis was observed. After fourth week of treatment levels of γ-H2AX decreased significantly in the group with severe mucositis and increased in patients with mild side effects. The observed difference was not caused by the decrease in peripheral lymphocyte count, which was similar in both groups.ConclusionsPresented results indicate that severity of radiation-induced mucositis does not correlate directly with γ-H2AX levels measured in vivo in PBL. Prediction of mucositis grade based on γ-H2AX level is not yet possible, either before treatment or early during treatment, but preliminary results, indicating significant differences in γ-H2AX kinetics between groups, encourage further studies.

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