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: 10747068
• 负责人: Sam C. Wang
• 金额: $ 6.29万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747068
• 关键词: Accounting; Age; Behavior; Benign; Biology; CDH1 gene; Cancer Patient; Characteristics; Diagnosis; Diffuse gastric cancer; Disease; Disparity; Early Diagnosis; Enrollment; Environmental Exposure; Face; Genetic; Genomics; Heterogeneity; High Prevalence; Hispanic; In Vitro; Incidence; Inherited; Latino; Latino Population; Life; Life Style; Methods; Mission; Modification; Molecular; Not Hispanic or Latino; Obesity; Onset of illness; Outcome; Pathogenicity; Patients; Penetrance; Prevalence; Prevention; Public Health; Recommendation; Research; Research Personnel; Role; Screening for Gastric Cancer; Syndrome; System; Testing; United States National Institutes of Health; Variant; Work; cancer health disparity; clinical epidemiology; clinically actionable; experience; gene environment interaction; genetic testing; in vivo; innovation; lifetime risk; malignant stomach neoplasm; novel; outcome disparities; parent grant; tool

PARENT GRANT 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 incomplete. 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.

家长资助项目摘要/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 与非西班牙裔白人相比，患有 GC 的 Hs/L 患者的公共卫生问题尚未得到充分研究和解决。 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 这种差异的分子原因尚不清楚，因为 Hs/L 患者尚不清楚。 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%（通常在年轻时），因此，Hs/L 患者的风险可能更高。 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，因此迫切需要将 Hs/L 患者中的 HDGC 患病率定义为 该综合征可能是 GC 健康差异的一个原因，但是 HDGC 的真实发生率的确定尚不确定。 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 个中的 3 个具有不确定的功能），以及 2）CDH1 变异的外显率 虽然肥胖与 GC 的诊断有关，但研究人员的初步工作尚不完整。 表明肥胖还可能通过诱导疾病早期发作来影响疾病外显率。 该提议旨在确定 GC 健康差异的分子机制。假设是较高的。 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，这是一个融合了临床流行病学和临床流行病学的创新转化项目。 将进行实验生物学以实现以下目标：确定疾病的患病率。 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 目标 2 将招募来自世界各地的患有弥漫性 GC 的白人患者进行功能评估。 使用体外和体内系统发现的 CDH1 变异是否会赋予致病行为。 将确定肥胖对 CDH1 变异外显率的影响 该项目的创新点是：1）解释。 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，以及 3) 研究肥胖作为 GC 外显率的修饰因素对预期结果的影响。 这将是确定 GC 健康差异的第一个已知分子机制。 肥胖增加 CDH1 外显率将为基因与环境相互作用开辟新的研究方向 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，60% 的 HDGC。 病例没有已知原因；所提出的方法可用于测试其他潜在的 HDGC 原因。