Determining the role of germline CDH1 variants in gastric cancer outcome disparities in Hispanic/Latino patients

确定种系 CDH1 变异在西班牙裔/拉丁裔患者胃癌结果差异中的作用

• 批准号: 10652648
• 负责人: Sam C. Wang
• 金额: $ 65.22万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652648
• 关键词: Accounting; Age; Automobile Driving; Behavior; Benign; Biological Assay; Biology; CDH1 gene; Cancer Patient; Cell Adhesion Molecules; Cell Line; Characteristics; Data; Development; Diagnosis; Diet; Diffuse gastric cancer; Disease; Disparity; E-Cadherin; Early Diagnosis; Engraftment; Enrollment; Environmental Exposure; Epidemiology; Epidermal Growth Factor Receptor; Face; Genetic; Genomics; Growth; Guidelines; Helicobacter Infections; Heterogeneity; High Prevalence; Hispanic; In Vitro; Incidence; Inflammatory Response; Inherited; Latino; Latino Population; Life; Life Style; Logistic Regressions; Loss of Heterozygosity; Malignant Neoplasms; Masks; Methods; Mission; Modeling; Modification; Molecular; Not Hispanic or Latino; Obese Mice; Obesity; Onset of illness; Organoids; Outcome; Pathogenicity; Pathway interactions; Patients; Penetrance; Phenotype; Population Heterogeneity; Prevalence; Prevention; Public Health; Publishing; Recommendation; Registries; Research; Research Personnel; Risk; Role; Sampling; Screening for Gastric Cancer; Signal Transduction; Syndrome; System; Testing; Thinness; Transgenic Mice; United States National Institutes of Health; Variant; Work; cancer health disparity; clinical epidemiology; clinically actionable; cohort; early onset; exome sequencing; experience; gastric organoids; gene environment interaction; genetic testing; health difference; high risk; in vitro Assay; in vivo; in vivo Model; innovation; lifestyle factors; lifetime risk; malignant stomach neoplasm; multidisciplinary; novel; obese patients; outcome disparities; participant enrollment; protein expression; tool; tumor; tumor growth; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT The molecular basis of gastric cancer (GC) health disparities that Hispanic/Latino (Hs/L) patients face is an understudied and unmet public health issue. Compared to non-Hispanic Whites, Hs/L patients with GC are younger, have twice the disease incidence, and are more likely to develop the more aggressive form of the disease called diffuse GC. The molecular causes for these disparities are unknown since Hs/L patients have not been included in previous GC studies. The investigators recently completed the first integrated genomic analysis of Hs/L GC patients and found that 7 of 43 (16%) Hs/L patients with diffuse GC carried germline CDH1 variants. Germline CDH1 variants that are pathogenic cause hereditary diffuse GC syndrome (HDGC), which confers up to an 80% lifetime risk of developing diffuse GC, often at a young age. Thus, Hs/L patients may have a higher rate of HDGC, which would help explain the unique clinicopathologic characteristics seen in these patients since HDGC is thought to cause <1% of GC. There is a critical need to define HDGC prevalence in Hs/L patients as the syndrome may be a cause of GC health disparities. However, determination of the true rate of HDGC is hampered by two obstacles: 1) current tools are unable to determine if most CDH1 variants are pathogenic or benign (3 of 7 variants identified in Hs/L patients had uncertain function), and 2) the penetrance of CDH1 variants is unpredictable. While obesity is associated with being diagnosed with GC, preliminary work by the investigators shows that obesity may also influence disease penetrance by inducing earlier disease onset. The objective of this proposal is to identify molecular mechanisms for GC health disparities. The hypothesis is that a higher prevalence of HDGC and effect modification by obesity contribute to worse outcomes in Hs/L patients with GC compared to White patients. An innovative translational project that blends clinical epidemiology and experimental biology will be performed to pursue the following aims. Aim 1 will determine the prevalence of CDH1 variants and how they associate with genetic ancestry and lifestyle/environmental exposures in Hs/L and White patients with diffuse GC. Hs/L patients will be enrolled from around the world. Aim 2 will functionally assess whether discovered CDH1 variants confer pathogenic behavior using both in vitro and in vivo systems. Aim 3 will ascertain the effect of obesity on CDH1 variant penetrance. The project's innovations are: 1) accounting for the heterogeneity of the Hs/L population, 2) using novel functional methods to ascertain the pathogenicity of CDH1 variants, and 3) studying obesity as a modifier of GC penetrance. The impact of the expected results would be the identification of the first known molecular mechanism for GC health disparities. Determining that obesity augments CDH1 penetrance would open novel lines of inquiry into gene-environment interactions that drive GC formation. The results could be clinically actionable by informing genetic testing criteria and lifestyle recommendations that enable the prevention or early detection of diffuse GC in Hs/Ls. Finally, 60% of HDGC cases have no known cause; the proposed methods can be applied to test other potential HDGC causes.

项目概要/摘要 西班牙裔/拉丁裔 (Hs/L) 患者面临的胃癌 (GC) 健康差异的分子基础是 未得到充分研究和未得到解决的公共卫生问题。与非西班牙裔白人相比，患有 GC 的 Hs/L 患者 更年轻，发病率是其两倍，并且更有可能发展为更具侵袭性的形式 称为弥漫性GC的疾病。这些差异的分子原因尚不清楚，因为 Hs/L 患者尚未了解 已被纳入之前的 GC 研究中。研究人员最近完成了首次整合基因组分析 研究人员对 Hs/L GC 患者进行了研究，发现 43 名患有弥漫性 GC 的 Hs/L 患者中有 7 名 (16%) 携带种系 CDH1 变异。 种系 CDH1 变异可导致遗传性弥漫性 GC 综合征 (HDGC)，从而导致 一生中发生弥漫性胃癌的风险为 80%，通常是在年轻时。因此，Hs/L 患者可能具有较高的 HDGC 的发生率，这将有助于解释自这些患者以来所见的独特临床病理特征 HDGC 被认为导致 <1% 的 GC。迫切需要将 Hs/L 患者的 HDGC 患病率定义为 该综合征可能是 GC 健康差异的一个原因。然而，HDGC 真实率的测定是 受到两个障碍的阻碍：1）当前的工具无法确定大多数 CDH1 变异是否具有致病性或 良性（Hs/L 患者中发现的 7 个变异中的 3 个具有不确定的功能），以及 2）CDH1 变异的外显率 是不可预测的。虽然肥胖与 GC 的诊断有关，但研究人员的初步工作 研究表明，肥胖还可能通过诱发较早的疾病发作来影响疾病的外显率。的目标 该提案旨在确定 GC 健康差异的分子机制。假设较高 HDGC 的患病率和肥胖导致的效应改变导致 Hs/L GC 患者预后较差 与白人患者相比。一个融合临床流行病学和 将进行实验生物学以实现以下目标。目标 1 将确定 CDH1 变异以及它们如何与 Hs/L 和 Hs/L 的遗传血统和生活方式/环境暴露相关 患有弥漫性GC的白人患者。 Hs/L 患者将从世界各地招募。目标 2 将进行功能评估 使用体外和体内系统发现的 CDH1 变异是否会赋予致病行为。目标 3 将确定肥胖对 CDH1 变异外显率的影响。该项目的创新点是：1） Hs/L 群体的异质性，2) 使用新的功能方法来确定 Hs/L 群体的致病性 CDH1 变体，3) 研究肥胖作为 GC 外显率的调节因素。预期结果的影响 这将是第一个已知的 GC 健康差异分子机制的鉴定。确定 肥胖增加 CDH1 外显率将为基因-环境相互作用开辟新的探究途径 驱动GC形成。通过告知基因检测标准和生活方式，结果可以在临床上发挥作用 能够预防或早期检测 Hs/L 中弥漫性 GC 的建议。最后，HDGC的60% 病例原因不明；所提出的方法可用于测试其他潜在的 HDGC 原因。