Identifying new drivers of ovarian cancer from the non-coding genome by converging germline risk variants and somatic mutations

通过融合种系风险变异和体细胞突变，从非编码基因组中识别卵巢癌的新驱动因素

• 批准号: 10322728
• 负责人: Pei-Chen Peng
• 金额: $ 22.66万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322728
• 关键词: Advisory Committees; Affect; Area; BRCA1 gene; Binding Sites; Biological Assay; Buffers; California; Cancer Biology; Cell physiology; Cessation of life; ChIP-seq; Chromatin; Clinical; Code; Collaborations; Complex; Computer Models; Computing Methodologies; DNA Sequence; DNA Sequence Alteration; Data; Data Science; Data Set; Development; Disease; Elements; Enhancers; Ensure; Environment; Epithelial ovarian cancer; Etiology; Faculty; Fellowship; Fostering; Future; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomic Segment; Genotype; Germ-Line Mutation; Goals; Grant; Heritability; Human Genetics; Interdisciplinary Study; Intervention; Knowledge; Knowledge acquisition; Laboratories; Learning; Los Angeles; Machine Learning; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Medical center; Mentors; Modeling; Molecular Profiling; Mutation; Nature; Noise; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Ovarian; Penetrance; Phenotype; Positioning Attribute; Prevention approach; Process; Productivity; Prognosis; Proteins; Regulatory Element; Research; Research Personnel; Research Proposals; Research Training; Science; Series; Somatic Mutation; Susceptibility Gene; TP53 gene; Techniques; Technology; Training; Training Programs; Transcriptional Regulation; Tumor Tissue; Universities; Untranslated RNA; Variant; cancer genetics; cancer genomics; cancer initiation; cancer predisposition; cancer type; career development; case control; cell type; clinical translation; cohort; complex biological systems; epigenetic regulation; epigenomics; experience; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic data; histone modification; improved; insight; machine learning model; mortality; multiple omics; next generation sequencing; novel; ovarian neoplasm; population based; precursor cell; professor; promoter; risk variant; success; tenure track; transcription factor; tumor; tumor progression; tumorigenesis; whole genome

PROJECT SUMMARY/ABSTRACT The goal of the proposed research training program is to provide tailored additional training to facilitate successful career development throughout the completion of postdoctoral fellowship and the transition to independent tenure track professor. The key elements of this plan are: Candidate: I have considerable research experience in developing and applying computational models to understand complex biological systems. The training component of this proposal will focus on acquisition of knowledge in cancer genetics and genomics, integrative computational methodologies, and next-generation sequencing technologies. Additionally, I will receive training in laboratory management, networking and collaborations, and grant submissions. This well-rounded training plan will accelerate my goals of being an independent researcher and developing computational models to better understand cancer biology. Environment: The training environment at Cedars-Sinai Medical Center fosters productivity and collaboration with world class researchers in clinical and basic biomedical science. I have assembled an advisory committee with esteemed experts in the areas of epigenomics, genetics, data science and cancer biology to ensure my success in this training program and to guide me through the successful acquisition of a tenure track faculty position. These include my mentor Dr. Simon Gayther and four advisors, Dr. Benjamin Berman and Dr. Shelly Lu from Cedars-Sinai, and Dr. Bogdan Pasaniuc, and Dr. Paul Boutros from University of California, Los Angeles. Research: A fundamental goal of human genetics is to decipher the relationship between genotype and phenotype. Cancer is a disease comprising a heritable component that confers cancer predisposition and an acquired (somatic) component where accumulation of genetic alterations occurs during disease development. Population based genome-wide association studies (GWAS) and whole genome sequencing (WGS) analyses have identified thousands of germline risk variants and somatic non-coding mutations involved in ovarian cancer development. Often, protein-coding cancer driver genes harbor both deleterious germline risk variants and somatic mutations. This proposal hypothesizes that the same is true for non-coding cancer drivers. With the wealth of epigenomics and regulatory datasets, the goal is to identify genomic regions where there are interactions between germline and somatic variants. The specific aims are: (1) identify functional regulatory elements where non-coding germline and somatic ovarian cancer variants co-localize; (2) identify non-coding ovarian cancer drivers through multi-omics regulatory evidence by machine learning models. The proposed studies will establish systematic and quantitative models to identify ovarian cancer non-coding drivers and improve our understanding of disease etiology.

项目总结/文摘