Metagenomic profiling of oral polymicrobial flora in head and neck cancers

头颈癌口腔多微生物菌群的宏基因组分析

基本信息

批准号：
8142045
负责人：
Charis Eng
金额：
$ 68.34万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-13 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142045
关键词：
ABCB1 gene Achievement Acute Disease Address Age Algorithms Antibiotics Apoptosis Awareness Back Bacteria Cancer Detection Cell Line Cellular Morphology Chronic Chronic Obstructive Airway Disease Clinical Consumption DNA Damage DNA Methylation Data Deglutition Dental Hygiene Development Diagnosis Discipline of Nursing Disease Drug Metabolic Detoxication Early Diagnosis Enzymes Epigenetic Process Epithelial Cells Evaluation Event Future Gene Mutation Gene Silencing Genes Genomics Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Health Hearing Helicobacter pylori Human Microbiome Hypermethylation IL8 gene Immune Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Cancer Lead Link MXI1 gene Malignant Epithelial Cell Malignant Neoplasms Metagenomics Methylation Modeling Mucous Membrane Operative Surgical Procedures Oral Oral cavity Oropharyngeal Outcome Pathogenesis Patients Periodontitis Poison Polycomb Population Prevention Prevention education Probiotics Process Quality of life Radiation Refractory Disease Research Resources Role Sampling Screening procedure Smell Perception Staging Stomach System Technology Time Tobacco Tumor Suppression Tumor Suppressor Genes United States United States National Institutes of Health Up-Regulation Variant base cancer initiation carcinogenesis chemokine chemotherapy cigarette smoking demethylation early onset gastrointestinal epithelium innovation interest knock-down malignant stomach neoplasm microbial overexpression population based promoter public health relevance response tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): When H. pylori in the stomach was linked with gastric cancer, and its eradication associated with regression, a paradigm-shifting model of carcinogenesis was created. Many bacterial species normally reside in various regions of the oropharyngeal mucosa, and may fluctuate depending on the host's age and dietary consumption. Interestingly, the incidence of head and neck squamous cell carcinoma (HNSCC) has been shown to correlate with dental hygiene, which may suggest the relevance of bacteria in the pathogenesis of this particular malignancy. Some bacteria can result in inflammation, which can cause increased methylation. Using genomic technology, we have demonstrated a possible link between HNSCC and specific bacterial populations based on their metagenomic profiles. Notably, we have proof-of-principle association between the presence of particular bacterial subpopulations per metabiomic profiling and MDR1 methylation status in HNSCC. We therefore hypothesize that specific bacterial subpopulations, as revealed by metagenomic profiling, can trigger targeted methylation events which then initiate HNSCC genesis and/or progression. We plan to address this hypothesis via 3 broad aims: (1) To utilize most recent high throughput sequencing technologies to identify the bacterial subpopulations in the oropharyngeal mucosa associated with HNSCC tumor initiation, progression, and/or prevention, with the innovative sub-aim to explore if specific microbiomic profiles are part of the field effect seen in HNSCC; (2) To interrogate the specific microbial "consortia" influencing inflammation with consequent epigenetic alterations of target tumor suppressor genes in HNSCC; (3) To functionally validate the involvement of MAD2 and/or MDR1 in HNSCC tumor suppression. The resulting microbial populations as reflected by metagenomic profiles will be interrogated for correlation with exposure and clinical information and targeted methylation. Finally, we will functionally validate whether the targeted methylation is relevant in HNSCC tumorigenesis or a random methylation effect in response to inflammation. To address this, we will overexpress or knock-down MDR1 in HNSCC cell lines and examine any effect on growth, apoptosis, cell morphology, or differentiation. This study promises to reveal the relevance of specific head and neck bacterial flora to cancer initiation and progression. Interesting future directions include clinical screening for the presence of specific bacterial indicators in order to provide early cancer or pre-cancer detection and perhaps prevention, based on probiotics or antibiotics. With metabiomic profiles capable of distinguishing samples based on prior radiation exposure or chemotherapy, we will implement targeted screening and/or demethylation treatment for patients with refractory disease. This type of data will also point to larger roles for early detection, awareness education, and prevention from hygienists and nursing. PUBLIC HEALTH RELEVANCE: Over 500,000 new cases of head and neck cancers (HNSCC) are diagnosed worldwide annually, with more than 11,000 individuals/year succumbing to this aggressive malignancy in the United States alone; despite huge strides in research achievements in this topic, overall outcome has remained unchanged for over 3 decades for the majority of patients with advanced stages of this disease. Patients who receive aggressive surgery to remove the cancer have significant disfigurement and diminished quality of life, with impaired ability to swallow, smell, and hear. If successful, then our current proposal promises a new understanding of the role of specific subpopulations of bacteria in the mouth leading to inflammation which shuts off cancer-suppressing genes, thus leading to HNSCC. If true, then we can take advantage of our findings for the earliest diagnosis and even prevention with probiotic therapy. Importantly, even for advanced HNSCC or that which has spread, our findings will help point to antibiotics and agents that can turn back on the cancer-suppressing genes to revolutionize treatment.

描述（由申请人提供）：当胃中的幽门螺杆菌与胃癌相关，并且根除幽门螺杆菌与消退相关时，就创建了致癌作用的范式转变模型。许多细菌种类通常存在于口咽粘膜的各个区域，并且可能根据宿主的年龄和饮食消耗而波动。有趣的是，头颈鳞状细胞癌（HNSCC）的发病率已被证明与牙齿卫生相关，这可能表明细菌在这种特殊恶性肿瘤发病机制中的相关性。有些细菌会导致炎症，从而导致甲基化增加。利用基因组技术，我们根据宏基因组图谱证明了 HNSCC 与特定细菌群体之间可能存在的联系。值得注意的是，我们对 HNSCC 中每个代谢组学分析中特定细菌亚群的存在与 MDR1 甲基化状态之间的关联进行了原理验证。因此，我们假设宏基因组分析揭示的特定细菌亚群可以触发靶向甲基化事件，从而启动 HNSCC 的发生和/或进展。我们计划通过 3 个广泛的目标来解决这一假设：(1) 利用最新的高通量测序技术来识别与 HNSCC 肿瘤发生、进展和/或预防相关的口咽粘膜中的细菌亚群，其创新的子目标是探索特定的微生物组特征是否是 HNSCC 中观察到的场效应的一部分； (2) 探究影响 HNSCC 炎症的特定微生物“联合体”以及随之而来的靶肿瘤抑制基因的表观遗传改变； (3) 功能验证 MAD2 和/或 MDR1 在 HNSCC 肿瘤抑制中的作用。宏基因组图谱所反映的最终微生物种群将被询问与暴露和临床信息以及目标甲基化的相关性。最后，我们将从功能上验证靶向甲基化是否与 HNSCC 肿瘤发生相关或对炎症反应的随机甲基化效应是否相关。为了解决这个问题，我们将在 HNSCC 细胞系中过表达或敲低 MDR1，并检查对生长、凋亡、细胞形态或分化的影响。这项研究有望揭示特定头颈部细菌菌群与癌症发生和进展的相关性。未来有趣的方向包括对特定细菌指标的存在进行临床筛查，以便基于益生菌或抗生素提供早期癌症或癌前检测，甚至可能进行预防。凭借能够根据既往放射暴露或化疗区分样本的代谢组学特征，我们将为难治性疾病患者实施有针对性的筛查和/或去甲基化治疗。此类数据还将表明卫生人员和护理人员在早期检测、意识教育以及预防方面发挥着更大的作用。公共卫生相关性：全球每年诊断出超过 500,000 例头颈癌 (HNSCC) 新病例，仅在美国每年就有超过 11,000 人死于这种侵袭性恶性肿瘤；尽管该主题的研究取得了巨大进步，但三十多年来，大多数晚期该疾病患者的总体结果仍未改变。接受激进手术切除癌症的患者会出现严重毁容、生活质量下降、吞咽、嗅觉和听觉能力受损。如果成功，那么我们目前的提议有望对口腔中特定细菌亚群的作用产生新的认识，这些细菌会导致炎症，从而关闭抑癌基因，从而导致头颈部鳞状细胞癌。如果属实，那么我们可以利用我们的发现进行最早的诊断，甚至通过益生菌疗法进行预防。重要的是，即使对于晚期头颈部鳞状细胞癌或已经扩散的头颈部鳞状细胞癌，我们的研究结果也将有助于找到可以逆转癌症抑制基因的抗生素和药物，从而彻底改变治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hunting for cancer in the microbial jungle.

DOI：
10.1186/gm446
发表时间：
2013
期刊：
Genome medicine
影响因子：
12.3
作者：
Funchain P;Eng C
通讯作者：
Eng C

Bacteriome and mycobiome associations in oral tongue cancer.

DOI：
10.18632/oncotarget.21921
发表时间：
2017-11-14
期刊：
Oncotarget
影响因子：
0
作者：
Mukherjee PK;Wang H;Retuerto M;Zhang H;Burkey B;Ghannoum MA;Eng C
通讯作者：
Eng C

A novel method for determining microflora composition using dynamic phylogenetic analysis of 16S ribosomal RNA deep sequencing data.

DOI：
10.1016/j.ygeno.2011.04.002
发表时间：
2011-10
期刊：
GENOMICS
影响因子：
4.4
作者：
Chan, Ernest R.;Hester, James;Kalady, Matthew;Xiao, Hui;Li, Xiaoxia;Serre, David
通讯作者：
Serre, David

Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma.

DOI：
10.1093/hmg/ddr593
发表时间：
2012-04-01
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Bebek G;Bennett KL;Funchain P;Campbell R;Seth R;Scharpf J;Burkey B;Eng C
通讯作者：
Eng C

Microbiomic differences in tumor and paired-normal tissue in head and neck squamous cell carcinomas.

DOI：
10.1186/s13073-017-0405-5
发表时间：
2017-02-07
期刊：
Genome medicine
影响因子：
12.3
作者：
Wang H;Funchain P;Bebek G;Altemus J;Zhang H;Niazi F;Peterson C;Lee WT;Burkey BB;Eng C
通讯作者：
Eng C