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

家长助学金项目摘要/摘要 拉美裔/拉丁裔(HS/L)患者面临的胃癌(GC)健康差异的分子基础是 未得到充分研究和满足的公共卫生问题。与非西班牙裔白人相比，HS/L GC患者 更年轻，发病率是普通人的两倍，并且更有可能发展为更具侵袭性的 一种称为弥漫性GC的疾病。这些差异的分子原因尚不清楚，因为HS/L患者没有 已包括在以前的GC研究中。研究人员最近完成了第一个完整的基因组分析 并发现43例弥漫性GC患者中有7例(16%)携带CDH1基因突变。 致病的生殖系CDH1变异会导致遗传性弥漫性GC综合征(HDGC)，这会导致 患弥漫性GC的终生风险为80%，通常是在年轻时。因此，HS/L患者可能有更高的 HDGC的比率，这将有助于解释这些患者独特的临床病理特征 HDGC被认为是导致1%的GC的原因。迫切需要将HS/L患者中HDGC的患病率定义为 该综合征可能是造成GC健康差异的原因之一。然而，HDGC的真实比率的确定是 受到两个障碍的阻碍：1)目前的工具无法确定大多数CDH1变体是致病的还是 良性(在HS/L患者中发现的7个变异中有3个功能不确定)，2)CDH1变异的外显性 是不完整的。虽然肥胖与被诊断为GC有关，但研究人员的初步工作 研究表明，肥胖还可能通过导致更早的疾病发作来影响疾病外显性。的目标是 这项建议是为了确定GC健康差异的分子机制。假设是一个更高的 HDGC的患病率和肥胖的效应改变导致HS/L GC患者的不良预后 与白人患者相比。一个创新的翻译项目，将临床流行病学和 为了实现以下目标，将开展实验生物学研究。目标1将确定 CDH1变异及其与遗传祖先和生活方式/环境暴露的关联 弥漫性胃癌的白人患者。HS/L的患者将来自世界各地。目标2将从功能上评估 在体外和体内系统中，是否发现了CDH1变异体都会导致致病行为。目标3 将确定肥胖对CDH1变异外显率的影响。该项目的创新之处在于：1)占 HS/L群体的异质性，2)用新的功能方法确定Hs/Hs/Hs的致病性 CDH1变异体，以及3)研究肥胖作为GC外显性的修饰物。预期结果的影响 将是第一个已知的GC健康差异的分子机制的确定。确定 肥胖增加CDH1外显率将开启探索基因-环境相互作用的新途径 推动GC形成。通过告知基因测试标准和生活方式，这一结果可能在临床上可操作 能够预防或早期发现HS/L中弥漫性GC的建议。最后，60%的HDGC 病例没有已知的原因；建议的方法可以应用于测试其他潜在的HDGC原因。

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.