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A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC

MSI CRC 疾病外显率和进展中癌症衍生的截短突变

基本信息

批准号：
9885369
负责人：
Chengyu Liang
金额：
$ 19.05万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2020-06-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885369
关键词：
Address Adjuvant Chemotherapy Animal Model Appearance Autophagocytosis Behavior Biochemistry Biological Assay Cancer Etiology Cancer Patient Cell division Cells Centrosome Centrosome Pathway Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Colon Colorectal Cancer DNA Development Disease Dominant-Negative Mutation Down-Regulation Effectiveness Epithelial Epithelium Evolution Failure Fluorouracil Frameshift Mutation Gene Mutation Genes Genetic Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Image Individual Induced Mutation Infiltration Knock-in Knowledge Lesion Link Lymphocyte Malignant - descriptor Malignant Neoplasms Mediating Microsatellite Instability Microsatellite Repeats Mismatch Repair Mismatch Repair Deficiency Mismatch Repair Gene Inactivation Modeling Modification Molecular Molecular Biology Mucinous Differentiation Mus Mutagenesis Mutation Oncogenes Organoids Pathogenesis Pathologist Pathway interactions Patients Penetrance Pharmaceutical Preparations Phenotype Physiological Play Prognostic Marker Proteins Recurrence Research Personnel Risk Role Structure System Translations Tumor Suppressor Proteins Tumor-Associated Process Ursidae Family Validation base cancer genetics carcinogenesis cell motility cell transformation cohort colon cancer patients colorectal cancer treatment in vivo inhibition of autophagy innovation live cell imaging mortality multidisciplinary mutant mutant mouse model novel personalized medicine predictive marker single molecule therapeutic target three dimensional cell culture time use tumor tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary Colorectal cancer (CRC) ranks as the 2nd most common cause of cancer mortality. Nearly all patients suffering from Lynch Syndrome as well as 15-20% of patients with sporadic early CRC have microsatellite instability (MSI) due to DNA mismatch repair (MMR) deficiency. Notably, defective MMR by itself is not sufficient to drive cell transformation and tumorigenesis, but microsatellite mutations in a limited number of target genes might be positively selected during tumor development, underlying MSI-associated pathogenesis. Unfortunately, relatively little is known about the molecular underpinnings of MSI target genes and their mechanism of action in MSI-associated disease penetrance. This project will fill this gap, capitalizing on our recent discovery of a strong correlation between the MSI phenotype and recurrent frameshift (FS) mutation in the autophagy tumor suppressor UVRAG. The protein product of this FS mutation functions as an oncogene and a bona fide trigger of centrosome amplification (CA) in CRC. We now bring within this proposal a collaboration of leaders in CRC genetics and molecular biology along with clinicians and pathologists to understand the molecular mechanism by which CA augments the expressivity of MMR mutations, contributing to human colonic carcinogenesis. To achieve this goal, we propose three Specific Aims, including (1) identifying the molecular mechanism of CA in MSI CRC associated with UVRAGFS expression; (2) examining the impact of CA on the differentiation and metastatic capacity of MSI patient-derived colonic organoids; and (3) investigating the in vivo role of MSI-derived UVRAGFS in disease penetrance and cancer progression using targeted mutant mouse models. These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, live- cell imaging, and physiological assays in cells and in mice with targeted mutations in genes related to MMR deficiency and centrosome deregulation. We have access to the right cohort of patients and our use of patient-derived colonic organoids will maximize the relevance of our findings for eventual translation to cancer patients in the clinic. Together, we anticipate that our studies will delineate a novel mechanism underlying MSI-associated disease penetrance and provide compelling in vivo validation of CA as a novel prognostic and predictive biomarker and a therapeutic target for personalized treatment of MSI CRC including Lynch Syndrome.

项目总结