Immune and transcriptomic biomarkers of progressive oral premalignant lesions

进行性口腔癌前病变的免疫和转录组生物标志物

• 批准号: 10770711
• 负责人: Fatemeh Momen Heravi
• 金额: $ 74.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770711
• 关键词: Address; Alcohols; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Characteristics; Clinical; Code; Communities; Data; Data Set; Development; Diagnosis; Disease; Early Diagnosis; Early identification; Etiology; Fluorescence; Gene Combinations; Gene Expression; HPV-High Risk; Heterogeneity; Histologic; Histopathologic Grade; Human Papillomavirus; Immune; Immunologic Markers; Immunotherapy; Incidence; Individual; Knowledge; Lesion; Leukoplakia; Machine Learning; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Microscopic; Modality; Modeling; Molecular; Morbidity - disease rate; NCI-Designated Cancer Center; Oral; Oral Examination; Oral Leukoplakia; Oral Stage; Patients; Persons; Play; Population Heterogeneity; Prevention; Risk; Risk Assessment; Role; Specimen; Survival Rate; Tissues; Tobacco; Transcript; Translations; Tumor-associated macrophages; Universities; Untranslated RNA; Validation; biobank; biomarker identification; clinical biomarkers; clinical decision-making; cohort; conventional therapy; follow-up; high risk; improved; malignant mouth neoplasm; malignant oropharynx neoplasm; mortality; mouth squamous cell carcinoma; multidisciplinary; neoplastic; oral lesion; premalignant; progression marker; progression risk; racial diversity; recruit; response; risk prediction model; risk stratification; screening; survival outcome; transcriptome sequencing; transcriptomics; tumor; tumor-immune system interactions

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the 6th leading cause of cancer-related mortality worldwide. OSCC is curable with favorable survival outcomes if detected early. The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs) with oral leukoplakia or white lesions being the most common type. However, not all oral leukoplakia progresses to OSCC. Accurate identification of OPMDs that are likely to progress to OSCC offers the best strategy for OSCC prevention and management and can lead to decreasing patients’ morbidity and mortality through earlier detection. Although proven inadequate, microscopic examination and histological grading remain the gold standard for predication of malignant transformation. For instance, some low-grade OPMDs will progress to OSCC but not all high-grade OPMDs progress to OSCC. There is an urgent and unmet demand for highly efficacious biomarkers to identify progressive leukoplakias with a high risk of OSCC conversion. Addressing this knowledge gap can lead to early detection of HPV-negative OSCC and improve patient survival. Examining OPMDs with and without malignant transformation, we have found specific transcriptomic signatures which are associated with progressive OPMDs. Using spatial transcriptomics and multiplex immune fluorescence (mIF), we observed that malignantly transformed OPMDs have significantly increased immunosuppressive tumor-associated macrophages (enriched in ARG1) and low levels of CD8+ T- cells. Our central hypothesis is that the levels and trajectories of such signatures in tissues are predictive of the malignant conversion of OPMDs to OSCC. The primary objective of this multi-disciplinary U01 collaborative study is to identify and validate transcriptomic and immune signatures that can discriminate OPMDs predicted to malignantly progress and develop, validate, and refine a risk stratification model based on identified biomarkers and clinical variables. In Aims 1 and 2, we will leverage a well-characterized, racially diverse population of over 500 individuals with histologically confirmed OPMDs. We will validate our list of transcriptomic and immune-related biomarkers and perform RNA sequencing and spatial transcriptomics to identify potential additional transcripts associated with the malignant progression of OPMDs. In Aim 3, we will develop a combination risk score formula based on selected transcriptomics and immune biomarkers and clinicodemographic variables to predict OMPD malignant progression based on our internal cohort. We will validate the combination risk score formula in an independent cohort of 300 patients. The risk score formula can be used by clinicians for risk assessment and clinical decision making. The contribution from this project is expected to be significant as it can lead to introduction of a personalized risk stratification approach for management of OPMDs. Detecting preneoplastic lesions with high malignant transformation risk will substantially increase patient survival while maximizing OSCC screening benefits.

项目总结