A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection

Heß, Julia; Unger, Kristian; Maihöfer, Cornelius; Schüttrumpf, Lars; Wintergerst, Ludmila; Heider, Theresa; Weber, Peter; Marschner, Sebastian; Braselmann, Herbert; Samaga, Daniel; Kuger, Sebastian; Pflugradt, Ulrike; Baumeister, Philipp; Walch, Axel; Woischke, Christine; Kirchner, Thomas; Werner, Martin; Werner, Kristin; Baumann, Michaël; Budach, Volker; Combs, Stephanie E.; Debus, Jürgen; Grosu, Anca L.; Krause, Mechthild; Linge, Annett; Rödel, Claus; Stuschke, Martin; Zips, Daniel; Zitzelsberger, Horst; Ganswindt, Ute; Henke, Michael; Belka, Claus

doi:10.1158/1078-0432.ccr-18-0776

Cited by 59 publications

(60 citation statements)

References 48 publications

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“…Low numbers in the former smoker category but also the lack of more accurate smoking status values may have decreased the power to reveal the reported association with smoking (79,98,99). Since we focused on known determinants of radiation response, other biomarkers were not included despite their relevance or prognostic value in HNSCC (5,6,16,(100)(101)(102)(103)(104)(105)(106). Some, such as tumor mutational burden (TMB) are prevalent in laryngeal and HPV-negative pharyngeal HNSCC (14) but require DNA sequencing data.…”

Section: Discussionmentioning

confidence: 99%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 + T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). van der Heijden et al. HNSCC Biology Impacting Chemo-Radiotherapy Outcomes Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8 + T-cells: HR = 2.2, p < 0.05; CD8 + T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8 + Tcell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.

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Section: Discussionmentioning

confidence: 99%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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“…At present, lncRNAs and miRNAs are believed to play an important role in tumorigenesis and have been identified as potential prognostic markers for HNSCC. Yang et al [ 8 ] established an 8-lncRNA signature associated with the prognosis of HNSCC, and Hess et al [ 9 ] identified prognostic 5-miRNA signature to independently predict disease control and survival in HNSCC patients. However, autophagy, as a crucial mechanism in tumorigenesis and progression, has not been studied on the effect of autophagy-associated genes on the prognosis of HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

Cheng

Yuan

2020

Disease Markers

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Background. Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies in the world, with low survival and poor quality of life. Autophagy-associated genes (ATGs) have been reported to be involved in the initiation and progression of malignancies. Here, we aimed to investigate the association between autophagy-associated genes and the outcomes in HNSCC patients. Methods. We obtained ATGs with prognostic values by analyzing the datasets from The Cancer Genome Atlas (TCGA) and Human Autophagy Database (HADb). The enrichment functions of autophagy differential genes were analyzed by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The Kaplan-Meier method was applied to the survival curve analysis. A prognostic autophagy-related gene signature was established, and its independence was verified. Results. We acquired a total of 529 samples and 232 ATGs; further, we identified 45 genes associated with prognosis and built a prognosis autophagy signature based on risk score of 15 genes. Patients were divided into two groups based on risk scores. The Kaplan-Meier curve illustrated that the survival rate of the high-risk group was significantly lower than that of the low-risk group in both the training group and validation group. The ROC curve revealed that the risk score had the highest AUC value in the 3rd and 5th years, reaching 0.703 and 0.724, which are higher than other risk factors such as gender, age, and TNM stage. The nomogram further confirmed its weight in the prognosis of HNSCC patients. Through KEGG and GO enrichment analyses, we observed that ATGs were involved in the tumorigenesis and invasion of tumor by various mediating pathways. We gained 3 hub genes (MAP1LC3B, FADD, and LAMP1) and further analyzed the survival curves, mutations, differential expressions, and their roles in tumors on the online websites. Conclusion. We identified a novel autophagy-related signature that may provide promising biomarker genes for the treatment and prognosis of HNSCC. We need to validate its prognostic value by applying it to the clinic.

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“…A large portion of the studies regarded mRNA signatures (33/61) , while a minor portion of the studies considered miRNA signatures (11/61) [52][53][54][55][56][57][58][59][60][61][62] and other non-coding RNA signatures (13/61) [63][64][65][66][67][68][69][70][71][72][73][74][75][76]. Only 4/61 [77][78][79][80] studies identified signatures by a high-throughput omics analysis of methylated DNA.…”

Section: Analysis Of Recent Epigenomics and Transcriptomics Datamentioning

confidence: 99%

Transcriptomics and Epigenomics in head and neck cancer: available repositories and molecular signatures

et al. 2020

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For many years, head and neck squamous cell carcinoma (HNSCC) has been considered as a single entity. However, in the last decades HNSCC complexity and heterogeneity have been recognized. In parallel, high-throughput omics techniques had allowed picturing a larger spectrum of the behavior and characteristics of molecules in cancer and a large set of omics web-based tools and informative repository databases have been developed. The objective of the present review is to provide an overview on biological, prognostic and predictive molecular signatures in HNSCC. To contextualize the selected data, our literature survey includes a short summary of the main characteristics of omics data repositories and web-tools for data analyses. The timeframe of our analysis was fixed, encompassing papers published between January 2015 and January 2019. From more than 1000 papers evaluated, 61 omics studies were selected: 33 investigating mRNA signatures, 11 and 13 related to miRNA and other non-coding-RNA signatures and 4 analyzing DNA methylation signatures. More than half of identified signatures (36) had a prognostic value but only in 10 studies selection of a specific anatomical sub-site (8 oral cavity, 1 oropharynx and 1 both oral cavity and oropharynx) was performed. Noteworthy, although the sample size included in many studies was limited, about one-half of the retrieved studies reported an external validation on independent dataset(s), strengthening the relevance of the obtained data. Finally, we highlighted the development and exploitation of three gene-expression signatures, whose clinical impact on prognosis/prediction of treatment response could be high. Based on this overview on omics-related literature in HNSCC, we identified some limits and strengths. The major limits are represented by the low number of signatures associated to DNA methylation and to non-coding RNA (miRNA, lncRNA and piRNAs) and the availability of a single dataset with multiple omics on more than 500 HNSCC (i.e. TCGA). The major strengths rely on the integration of multiple datasets through meta-analysis approaches and on the growing integration among omics data obtained on the same cohort of patients. Moreover, new approaches based on artificial intelligence and informatic analyses are expected to be available in the next future.

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A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection

Abstract: The five-miRNA-signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC.

Cited by 59 publications

References 48 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

Transcriptomics and Epigenomics in head and neck cancer: available repositories and molecular signatures

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