Role of genetic and epigenetic alterations in CFTR in colorectal cancer

CFTR 遗传和表观遗传改变在结直肠癌中的作用

• 批准号: 10302894
• 负责人: Anna Prizment
• 金额: $ 22.93万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-26 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302894
• 关键词: Academic Medical Centers; Affect; Age; American; Animal Model; Animals; Automobile Driving; BRAF gene; Cancer Burden; Cancer Etiology; Cessation of life; Characteristics; Classification; Clinical; Code; Collaborations; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Methylation; Data; Data Set; Delta F508 mutation; Disease; Disease-Free Survival; Epigenetic Process; Functional disorder; Future; Gene Expression; Gene Frequency; General Population; Genes; Genetic; Heterozygote; Human; Hypermethylation; Incidence; Individual; Inherited; Intervention; Intestines; Ion Channel Protein; Knock-out; Lead; Link; Lung; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Methylation; Minor; Molecular; Mus; Mutation; Participant; Pilot Projects; Population Study; Prevalence; Prognosis; Publishing; Regulator Genes; Reporting; Risk; Role; Sampling; Single Nucleotide Polymorphism; Site; Societies; Stage at Diagnosis; Syndrome; Testing; The Cancer Genome Atlas; Time; Trans-Omics for Precision Medicine; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; base; biobank; cancer survival; colon cancer patients; colorectal cancer risk; colorectal cancer screening; cystic fibrosis patients; early screening; epidemiology study; exome sequencing; genetic epidemiology; genetic risk factor; genome sequencing; genome wide association study; genomic data; human model; human study; improved; insight; mortality; mouse model; mutant; mutational status; programs; promoter; screening; sex; targeted treatment; tumor; whole genome

SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. Despite advances in screening, ~50% of CRC cases are detected at later, less treatable stages. There is a need to identify new cancer-causing genetic alterations in CRC. Our group has recently shown a critical role for the cystic fibrosis transmembrane conductance regulator (CFTR) gene as a tumor suppressor in CRC. Epidemiological studies demonstrated that individuals with CF have six times greater risk of CRC than the general population, leading to recent classification of CF as a hereditary colon cancer syndrome. Further, our animal studies as well as a recent human study, suggested that heterozygous CF-carriers may also be at CRC risk. If confirmed, these findings have implications for the general population because more than 10 million Americans carry one copy of germline CF-causing mutations. In addition, we showed that lower CFTR expression in CRC tumors is associated with decreased overall and disease-free survival of CRC patients. In these tumors decreased CFTR expression is associated with increased promoter DNA methylation which suggests that DNA methylation may drive decreased CFTR expression in CRC tumors. Our central hypothesis is that germline and epigenetic alterations in the CFTR gene contribute to increased CRC risk and mortality. In Aim 1, we will determine associations of germline CFTR variants with CRC incidence and survival of CRC patients using existing genetic data, including high-quality whole genome sequencing, whole exome sequencing and genome-wide association studies, from large population-based studies – TOPMed, GECCO, and UK Biobank. In Aim 2, we will examine the association of DNA methylation in CFTR promoter with CFTR expression and survival of CRC patients using publically available data from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) datasets. The findings from this study could lead to CFTR mutation-based screening for early CRC detection in general population and testing CFTR-targeting therapies to improve survival of CRC patients with CFTR dysfunction.

总结 结直肠癌（CRC）是美国癌症相关死亡的第二大原因。 在筛查中，约50%的CRC病例在较晚、较难治疗的阶段被发现。有必要确定新的 导致癌症的基因改变。我们的团队最近显示了囊性纤维化的关键作用， 跨膜传导调节因子（CFTR）基因在结直肠癌中的抑癌作用。流行病学研究 研究表明，CF患者患CRC的风险是普通人群的6倍， 最近将CF分类为遗传性结肠癌综合征。此外，我们的动物研究以及 最近的人类研究表明，杂合CF携带者也可能有CRC风险。如果得到证实，这些 研究结果对一般人群有影响，因为超过1000万美国人携带一份拷贝， 导致CF的生殖细胞突变此外，我们发现CRC肿瘤中CFTR的低表达与肿瘤的恶性程度有关。 与CRC患者总体和无病生存率降低相关。在这些肿瘤中，CFTR降低 表达与启动子DNA甲基化增加有关，这表明DNA甲基化可能 驱动CRC肿瘤中CFTR表达降低。我们的核心假设是生殖系和表观遗传 CFTR基因的改变导致CRC风险和死亡率增加。在目标1中，我们将确定 生殖系CFTR变异与CRC发病率和CRC患者生存率的相关性， 遗传数据，包括高质量的全基因组测序、全外显子组测序和全基因组测序 相关性研究，来自大型人群研究- TOPMed、GECCO和UK Biobank。在目标2中， 将研究CFTR启动子DNA甲基化与CFTR表达和CRC生存的关系 使用来自癌症基因组图谱计划（TCGA）和基因表达的临床可用数据， Omnibus（GEO）数据集。这项研究的结果可能会导致CFTR突变为基础的早期筛查， 在一般人群中检测CRC并测试CFTR靶向治疗以提高CRC患者的生存率 CFTR功能障碍