Translating gene-calcium interactions to precision medicine for colorectal cancer

将基因-钙相互作用转化为结直肠癌的精准医学

• 批准号: 9003793
• 负责人: QI DAI
• 金额: $ 63.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-07 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003793
• 关键词: Address; Adverse effects; Affect; Alleles; Calcium; Cancer Etiology; Candidate Disease Gene; Cessation of life; Chlorides; Colon; Colonoscopy; Colorectal Adenoma; Colorectal Cancer; Consumption; DNA Resequencing; Dinoprostone; Disease; Endoscopy; Functional disorder; Gene Frequency; Genes; Genotype; Homeostasis; Hyperplastic Polyp; Hyperprostaglandin E syndrome; Incidence; Individual; Intervention; Italy; Joints; KCNJ1 gene; Kidney; Left; Link; Malignant Neoplasms; Measures; Minor; Molecular; Mutation; Myocardial; Natural History; PTH gene; Phase; Population; Potassium; Prevention strategy; Primary Prevention; Prostate; Recurrence; Regulation; Reporting; Resources; Risk; Serum; Side; Single Nucleotide Polymorphism; Sodium; Translating; United States National Institutes of Health; Variant; Vitamin D; absorption; adenoma; arm; base; calcium intake; cancer chemoprevention; carcinogenesis; cohort; driving force; epidemiology study; gene interaction; genetic variant; high risk population; hypercalciuria; individualized prevention; inward rectifier potassium channel; mortality; novel; precision medicine; prevent; prospective; public health relevance; rare variant; screening; wasting

DESCRIPTION (provided by applicant): Despite a reduction in both incidence and mortality of colorectal cancer, partially due to rapidly increased use of endoscopy, colorectal cancer (CRC) still remains the 4th most common incident cancer and the 2nd most common cause of cancer death in the US. Thus, it is critical to develop new primary prevention strategies. High consumption of calcium (Ca) has been linked to reduced risks of colorectal adenoma and CRC; however, results have been inconsistent. NKCC2, encoded by SLC12A1, is the direct downstream effector of ROMK encoded by KCNJ1. Both NKCC2 and ROMK serve as driving forces for reabsorption of Ca and Mg. Homozygous rare mutations in SLC12A1 and KCNJ1 cause type I and type II hyperprostaglandin E syndrome, respectively, both of which are characterized by marked hypercalcinuria (calcium wasting) and hyperprostaglandin E2 (high levels of PGE2). Over the past 5 years, in an NIH R01 project (AT004660, PI: Dai), we have examined single nucleotide polymorphisms (SNPs) in SLC12A1,and KCNJ1 and 12 other candidate genes which are critically involved in Ca and Mg (re)absorption and regulation, for interaction with intakes of Ca, Mg or Ca/Mg ratio in relation to colorectal adenoma risk. In this two-phase study, we identified and replicated 2 SNPs in KCNJ1 and SLC12A1 that significantly interacted with Ca intake in relation to colorectal adenoma risk, particularly multiple/advanced adenoma. In joint analysis of 2 genes, we observed highest Ca intake was not associated with risk among those with no variant alleles in 2 genes, but was significantly related to 39% and 69% reduced adenoma risk, among those who carry variant allele(s) in 1 and 2 genes, respectively. The corresponding reduction in risk with advanced or multiple adenomas was 89% among those with variant alleles in both genes. We also found similar findings in a third independent set of hyperplastic polyp cases vs. controls. We expanded to 10 more candidate genes and identified and replicated 1 SNP in SLC8A1 interacting with Ca in relation to adenoma risk. 38% of the US population have at least 1 variant allele in any 2 of 3 genes, among whom high Ca intake was associated with a 70% reduced adenoma risk. These findings are novel and promising. However, 3 SNPs in the Ca-gene interactions are non-functional tags. Also, we only examined tagging SNPs with a minor allele frequencye 5%, whereas rare mutations in these genes are causally linked to diseases with Ca homeostasis dysfunction. Furthermore, it is unknown if these interactions are associated with incident CRC or adenoma recurrence or confer additional protection from CRC in individuals receiving endoscopic screenings. The proposed study based on the unique resources available from PLCO will prospectively address these important questions. We propose to conduct targeted deep resequencing in these 3 genes to examine functional and rare SNPs and their interactions with Ca intake. In addition, we will conduct a molecular epidemiologic study to prospectively understand the mechanisms underlying these Ca-gene interactions.

描述（由申请人提供）：尽管结直肠癌的发病率和死亡率都降低了，部分原因是内窥镜检查的使用迅速增加，大肠癌（CRC）仍然是第四大常见的事件癌症，第二个最常见的癌症死亡原因在美国。因此，制定新的主要预防策略至关重要。高消耗钙（CA）已与结直肠腺瘤和CRC的风险降低有关。但是，结果不一致。由SLC12A1编码的NKCC2是由KCNJ1编码的ROMK的直接下游效应子。 NKCC2和ROMK都可以作为重吸收CA和MG的驱动力。 SLC12A1和KCNJ1中的纯合稀有突变分别导致I型和II型超植物素E综合征，这两种突变的特征在于明显的高钙尿（钙浪费）和高培养足蛋白E2（PGE2高水平）。在过去的5年中，在NIH R01项目（AT004660，PI：DAI）中，我们检查了SLC12A1中的单核苷酸多态性（SNP），而KCNJ1和KCNJ1和12个其他候选基因都严重涉及Ca和Mg（RE）吸收（RE）（RE）（RE）（RE）（RE）和调节，以与结直肠腺瘤风险有关的CA，Mg或Ca/Mg比的摄入量相互作用。在这项两阶段的研究中，我们在KCNJ1和SLC12A1中鉴定并复制了2个SNP，这些SNP与CA摄入量相对于结直肠腺瘤的风险，尤其是多/晚期腺瘤而与CA摄入显着相互作用。在对2个基因的联合分析中，我们观察到最高的Ca摄入量与2个基因无变异等位基因的风险无关，但与39％和69％的腺瘤风险降低显着相关，其中那些携带变异等位基因的人（S）分别为1和2基因。在这两个基因中具有变异等位基因的患者中，晚期或多个腺瘤的风险相应降低为89％。我们还发现，在第三组独立的增生息肉病例与对照组中发现了类似的发现。我们扩展到另外10个候选基因，并在SLC8A1中鉴定并复制了1个SNP与CA相互作用与腺瘤风险有关。 38％的美国人口在3个基因中的任何2个基因中至少具有1个变异等位基因，其中高CA摄入量与腺瘤风险降低了70％。这些发现是新颖而有前途的。但是，Ca-Gene相互作用中的3个SNP是非功能标签。同样，我们仅检查了以次要等位基因频率为5％的标记SNP，而这些基因的罕见突变与CA稳态功能障碍的疾病有因果关系。此外，未知这些相互作用是否与事件CRC或腺瘤复发有关，或者在接受内镜筛查的个体中赋予CRC的额外保护。根据PLCO提供的独特资源的拟议研究将前瞻性地解决这些重要问题。我们建议在这三个基因中进行有针对性的深度重新配置，以检查功能和稀有SNP及其与CA摄入的相互作用。此外，我们将进行一项分子流行病学研究，以前瞻性地了解这些CA-GEN相互作用的机制。