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; 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.

家长赠款项目摘要/摘要 西班牙裔/拉丁裔（HS/L）患者面对的胃癌（GC）健康分布的分子基础是一种 研究且未满足的公共卫生问题。与非西班牙裔白人相比，HS/L的GC患者为 年轻，有两倍的疾病事件，更有可能发展出更具侵略性的形式 疾病称为弥漫性GC。这些分布的分子原因是未知的，因为HS/L患者尚未 已包括在先前的GC研究中。研究人员最近完成了第一个综合基因组分析 在HS/L GC患者中，发现43例（16％）HS/L中有7例弥漫性GC患者携带种系CDH1变体。 病原性的种系CDH1变体导致遗传性弥漫性GC综合征（HDGC），它承认 通常在年轻时就有80％的终身风险。那，HS/L患者可能具有较高的 HDGC的速率，这将有助于解释这些患者在这些患者中看到的独特临床病理学特征 HDGC被认为会导致GC的1％。在HS/L患者中将HDGC患病率定义为迫切需要 该综合征可能是GC健康差异的原因。但是，确定HDGC的真实速率为 受两个障碍的阻碍：1）当前工具无法确定大多数CDH1变体是致病性还是 良性（在HS/L患者中鉴定出的7种变体中有3个具有不确定功能），2）CDH1变体的渗透率 是不完整的。尽管肥胖与被诊断为GC有关，但研究人员的初步工作 表明肥胖症也可能影响诱发的疾病发作。目的 该建议是确定GC健康差异的分子机制。假设是更高 HDGC的患病率和肥胖的效果修饰导致HS/L GC患者的预后较差 与白人患者相比。一个创新的翻译项目，将临床流行病学和 实验生物学将进行以下目标。 AIM 1将确定 CDH1变体及其如何与HS/L和 弥漫性GC的白人患者。 HS/L患者将从世界各地招收。 AIM 2将在功能上评估 是否使用体外和体内系统都会发现CDH1变体会议致病行为。目标3 将确定肥胖对CDH1变体渗透的影响。该项目的创新是：1）考虑 HS/L种群的异质性，2）使用新型功能方法来确定的致病性 CDH1变体和3）将肥胖症作为GC渗透的修饰剂研究。预期结果的影响 将是GC健康分布的第一个已知分子机制的鉴定。确定这一点 肥胖增强CDH1的渗透率将开启对基因环境相互作用的新型调查线， 驱动GC组。通过告知基因测试标准和生活方式，可以在临床上起作用。 建议在HS/LS中预防或早期检测到弥漫性GC的建议。最后，HDGC的60％ 案件没有已知原因；提出的方法可用于测试其他潜在的HDGC原因。