Role of genetic and epigenetic alterations in CFTR in colorectal cancer

摘要 结直肠癌(CRC)是美国癌症相关死亡的第二大原因，尽管在 筛查中，约50%的结直肠癌病例是在较晚、较难治疗的阶段被发现的。有必要确定新的 结直肠癌中致癌的基因改变。我们小组最近显示了囊性纤维化的关键作用。 跨膜电导调节基因在结直肠癌中的抑癌作用流行病学研究 结果表明，患有CF的个体患CRC的风险是普通人群的6倍，领先 最近将CF归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，杂合子的CF携带者也可能有结直肠癌的风险。如果得到证实，这些 这一发现对普通民众有影响，因为超过1000万美国人携带一份 生殖系致病突变的基因。此外，我们还发现在结直肠癌中CFTR的低表达是 与结直肠癌患者总体和无病生存率下降有关。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 DRIVE降低了结直肠癌中CFTR的表达。我们的中心假设是生殖系和表观遗传学 CFTR基因的改变增加了结直肠癌的风险和死亡率。在目标1中，我们将确定 生殖系CFTR变异与使用现有基因的结直肠癌患者的结直肠癌发病率和生存期的关系 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 协会研究，来自大型人口研究-TOPMed、GECCO和英国生物库。在目标2中，我们 我将研究cftr启动子DNA甲基化与cftr表达和结直肠癌生存的关系。 使用来自癌症基因组图谱计划(TCGA)和基因表达的公开数据的患者 综合(GEO)数据集。这项研究的发现可能导致基于CFTR突变的早期筛查 在普通人群中检测结直肠癌并测试CFTR靶向治疗以提高结直肠癌患者的存活率 伴有CFTR功能障碍。

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.