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

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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.