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

专利授权项目概要/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一个 未得到充分研究和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 年轻，有两倍的疾病发病率，更有可能发展为更具侵略性的形式， 一种叫做弥漫性胃癌的疾病这些差异的分子原因是未知的，因为Hs/L患者没有 已纳入既往GC研究。研究人员最近完成了第一个综合基因组分析 结果发现43例弥漫型GC患者中7例（16%）携带生殖系CDH 1变异。 致病性的种系CDH 1变体引起遗传性弥漫性GC综合征（HDGC）， 80%的终生风险发生弥漫性GC，通常在年轻时发生。因此，Hs/L患者可能具有更高的 HDGC的发生率，这将有助于解释这些患者中观察到的独特临床病理特征， HDGC被认为是导致<1%的GC。目前迫切需要将Hs/L患者的HDGC患病率定义为 该综合征可能是GC健康差异的原因。然而，HDGC的真实速率的确定是 受到两个障碍的阻碍：1）目前的工具不能确定大多数CDH 1变体是否是致病性的，或者 良性（在Hs/L患者中鉴定的7种变体中有3种功能不确定），和2）CDH 1变体的突变率 不完整虽然肥胖与被诊断为GC有关，但研究人员的初步工作 表明肥胖也可能通过诱导早期发病而影响疾病的发病率。的目标 这个建议是为了确定GC健康差异的分子机制。假设是， HDGC的患病率和肥胖对HDGC的影响导致Hs/L GC患者的预后更差 与白色患者相比。一个创新的转化项目，融合了临床流行病学和 实验生物学将进行追求以下目标。目标1将决定 CDH 1变异以及它们如何与Hs/L的遗传祖先和生活方式/环境暴露相关， 弥漫性GC的白色患者。HS/L患者将从世界各地入组。目标2将在功能上评估 发现的CDH 1变体是否使用体外和体内系统赋予致病行为。目标3 将确定肥胖对CDH 1变异体表达率的影响。该项目的创新点是：1）会计 Hs/L群体的异质性，2）使用新的功能方法来确定致病性 CDH 1变异，和3）研究肥胖作为GC突变的调节剂。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鉴定。确定 肥胖增加了CDH 1的表达，这将为研究基因-环境相互作用开辟新的途径， 驱动GC形成。通过告知基因检测标准和生活方式，结果可以在临床上采取行动 建议，使预防或早期检测弥漫性GC在H/L。最后，HDGC的60% 病例没有已知的原因;所提出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.