Functional characterization of 2q22.1 deletion in oral squamous cell carcinoma

口腔鳞状细胞癌2q22.1缺失的功能特征

• 批准号: 10669010
• 负责人: Ramin Farhad
• 金额: $ 5.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2024-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669010
• 关键词: 17p; Affect; Alcohol consumption; Apoptotic; Behavior; Biochemical; Biological Assay; CASP3 gene; CDKN2A gene; CRISPR/Cas technology; Cell Cycle; Cell Line; Cell Separation; Cells; Cervix Uteri; Chromosome Deletion; Clinical; Copy Number Polymorphism; DNA; Data; Development; Disease; Elements; Esophagus; Event; Frequencies; Gene Expression; Genes; Genetic Transcription; Growth; Human; Human Papillomavirus; Immunotherapy; In Vitro; Infection; Intervention; Investigation; LDL-Receptor Related Protein 1; Lung; Maintenance; Malignant Neoplasms; Modality; Molecular Biology Techniques; Mutation; Normal Cell; Operative Surgical Procedures; Oral; Oral cavity; Outcome; Patients; Pattern; Phenotype; Point Mutation; Population; Proliferating; Property; Radiation; Reporting; Sampling; Series; Site; Smoking; Sorting; Squamous Epithelium; Squamous cell carcinoma; TP53 gene; Therapeutic; Tissue-Specific Gene Expression; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumorigenicity; cancer cell; carcinogenesis; chemotherapy; genomic locus; high risk; in vitro Assay; keratinocyte; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; novel strategies; novel therapeutics; oral behavior; transcriptome sequencing; tumor; tumorigenic

PROJECT SUMMARY/ABSTRACT Oral squamous cell carcinoma (OSCC) affects approximately 350,000 patients worldwide. The primary causes of OSCC include smoking, consumption of alcoholic beverages, and infections with high-risk human papillomaviruses (HPV). Currently, the main therapeutic modalities offered to patients include surgery, radiation, chemotherapy, and immunotherapy. Despite the existing clinical interventions, the mortality for this disease remains approximately 20% and is greater for higher grade tumors. OSCC tumors are genetically heterogenous with a high rate of point mutations and somatic copy number variations (CNVs). Similar CNV patterns are commonly observed in other squamous cell carcinomas such as those arising from the lung, cervix, and esophagus. The CNVs also have a high propensity for co-occurring with inactivating mutations of tumor suppressor genes. However, despite discoveries documenting the presence of various genomic loci undergoing copy number alterations, the mechanistic contributions of these CNVs to OSCC carcinogenesis have yet to be determined. The early and most frequent genetic alterations in OSCC include loss of tumor suppressors CDKN2A (residing at 9p) in conjunction with mutations in TP53 (residing at 17p). Additionally, one of the most commonly deleted sites within OSCC tumors is located at 2q22.1. This deletion is entirely contained within the low-density lipoprotein receptor-related protein 1B gene, LRP1B, which has been implicated as a tumor suppressor in other cancers but has not been characterized in OSCC. Although deletions at this locus occur more frequently than would be expected by chance, inactivating point mutations within this gene are not common. Moreover, LRP1B is not expressed in oral keratinocytes, raising the question as to why the deletions at this locus occur at such a high frequency, despite the lack of gene expression. This suggests these deletions act by a mechanism that is independent of interfering with LRP1B function. Therefore, I hypothesize that chromosomal deletions at 2q22.1 act as driver events in OSCC progression via alteration of intragenic elements that function in tumor suppression. This proposal will address my hypothesis via three specific aims: 1) Determine the impact of 2q22.1 chromosomal deletions on the tumorigenic behavior of keratinocytes in vitro, 2) Identify mechanisms downstream of 2q22.1 deletion responsible for tumorigenic behavior, and 3) Identify the minimal critical region responsible for the observed phenotypic changes. These aims will be achieved utilizing a combination of biochemical and molecular biology techniques to create the deletions observed in patient samples in wild type keratinocytes and assess their contribution to tumorigenic behavior. Outcomes from this investigation will be used in the development of novel therapeutic applications for suppression of OSCC and potentially various other cancers that originate from the squamous epithelium.

项目总结/文摘