Mapping immuno-genomic drivers of the head and neck precancer invasive-disease transition

绘制头颈部癌前侵袭性疾病转变的免疫基因组驱动因素

• 批准号: 10770868
• 负责人: Ludmil B Alexandrov
• 金额: $ 79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770868
• 关键词: Address; Alcohol consumption; Atlases; Automobile Driving; Bioinformatics; CD3 Antigens; CD8B1 gene; Cd68; Cells; Chromosomal Gain; Chromosomal Instability; Clinical; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Epidemiology; Epithelium; Evaluation; Event; Formalin; Gene Expression; General Population; Genetic; Genome; Genomics; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histologic; Human Papillomavirus; Immune; Immunofluorescence Immunologic; Immunogenetics; Immunogenomics; Immunologic Surveillance; Infection; Intercept; Knowledge; Lesion; Leukoplakia; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Maps; Mediation; Modeling; Molecular; Morphology; Mutation; Natural History; Oral; Oral Leukoplakia; Paraffin Embedding; Patients; Persons; Population; Prevention; Process; Prospective cohort; Records; Resolution; Risk; Risk Factors; Role; Sampling; Screening for Oral Cancer; Structure; Subgroup; Surveys; Tissues; Tobacco use; Tumor Immunity; Whole Blood; anti-cancer; biobank; bioinformatics pipeline; cancer initiation; cohort; driver mutation; exome; exome sequencing; genomic data; immunogenic; immunoregulation; malignant mouth neoplasm; molecular marker; mouse model; mouth squamous cell carcinoma; neoplastic; novel; oral carcinogenesis; oral premalignancy; oral tissue; predictive marker; premalignant; prognostication; programmed cell death ligand 1; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Globally, more than 900,000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year, with more that 250,000 dying annually from this cancer. Infection with human papilloma virus (HPV), a known risk factor for developing HNSCC, significantly impacts clinical prognostication. Specifically, for HPV- negative HNSCC, the most lethal subtype of head and neck cancer, less than 30% of those diagnosed survive for more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamous cell carcinoma (OSCC). Importantly, most OSCCs are preceded by morphologically distinguishable pre- cancerous lesions which are readily accessible for histological and molecular evaluation. This provides a unique opportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversion of oral precancer into invasive OSCC. Oral leukoplakia, the focus of this application, represents the most frequent type of oral premalignancy, with one in every fifty people is expected to develop OL in their lifetime. OL’s low malignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses a major challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers. To address this challenge, we hypothesize that the evolutionary transition from an OL into an OSCC is due to the immuno-genomic interactions encompassing the acquisition of somatic driver events, the gain of chromosomal instability, and the loss of effective immunosurveillance. We further hypothesize that the genomic and immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ from those that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate the molecular and immune mechanisms by which OLs progress to OSCCs, and to develop actionable and predictive biomarkers. To achieve this objective, we will leverage well-annotated OL cohorts to generate the largest whole- exome and whole-transcriptome atlas encompassing 300 OLs, including at least 100 cancer progressors and 100 non-progressors. Further, by utilizing a spatial multiplex immuno-fluorescence platform and an unbiased RNA-sequencing approach for immuno-profiling, we will comprehensively map the immune landscapes of these 300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly, our state-of- the-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cell resolution in order to understand the role of common genomic alterations and immune surveillance in this process. Overall, this project will reveal the compendium of immuno-genetic changes that drive the evolutionary transition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immune surveillance mechanisms, which can likely halt this malignant transformation.

项目摘要 在全球范围内，超过90万人被诊断患有头颈部鳞状细胞癌（HNSCC） 每年有超过25万人死于这种癌症。人乳头瘤病毒（HPV）感染 已知的HNSCC发展风险因素，显著影响临床诊断。对于HPV- 阴性HNSCC是头颈癌中最致命的亚型，只有不到30%的确诊患者存活 五年多了最常见和致命的HPV阴性HNSCC亚型是口腔鳞状细胞癌 细胞癌（OSCC）。重要的是，大多数OSCC之前是形态学上可区分的前- 容易进行组织学和分子学评价的癌性病变。这提供了一个独特的 通过阻止这种致命癌症的转化， 口腔癌前病变转化为浸润性口腔鳞癌口腔白斑，重点是这种应用程序，代表最频繁的 口腔癌是口腔癌前病变的一种类型，预计每50人中就有1人在其一生中发展为OL。OL低 口腔癌的恶性转化率约为3.3%，其高度可变的自然史构成了 调查OL和拦截其恶性转化为浸润性口腔癌的主要挑战。 为了应对这一挑战，我们假设从OL到OSCC的进化转变是由于 免疫-基因组相互作用包括体细胞驱动事件的获得， 染色体不稳定和有效免疫监视的丧失。我们进一步假设， 和免疫景观OL的患者谁随后发展口腔癌（进展）将不同， 未发生口腔癌的患者（非进展者）。本项目的总体目标是阐明 OLs进展为OSCC的分子和免疫机制，并开发可操作和预测的 生物标志物。为了实现这一目标，我们将利用注释良好的OL队列来生成最大的整体- 外显子组和全转录组图谱涵盖300个OL，包括至少100个癌症进展者， 100名无进展者此外，通过利用空间多重免疫荧光平台和无偏免疫荧光分析， RNA测序方法的免疫分析，我们将全面绘制这些免疫景观， 300个OL，并将不同的免疫遗传学特征与可能进展为OSCC相关联。最后，我国- 将使用现有的口腔癌发生小鼠模型在单细胞水平上模拟OL向OSCC的转变 为了了解常见的基因组改变和免疫监视在这一过程中的作用， 过程总的来说，这个项目将揭示推动进化的免疫遗传变化的纲要。 从OL向OSCC的转变，并阐明一组可靶向的免疫细胞群和新的免疫细胞群。 监督机制，这可能会阻止这种恶性转变。