Abstract 565: CDX2 targets, GPA33 and LI-cadherin, are novel biomarkers with prognostic value in gastric cancer
Authors: Lopes Nair , Bergsland Christian , Bjornslett Merete , Bruun Jarle , Lothe Ragnhild , Almeida Raquel , David Leonor 
Published: August 2018

Abstract
Gastric cancer is one of the most common types of cancer and the third cause of cancer-related death worldwide. The aggressiveness of the disease is related to, among other factors, tumour differentiation. CDX2 is a known intestinal differentiation marker with prognostic value in gastric cancer and two of its targets are expressed at the cell surface: GPA33 (glycoprotein A33) and LI-cadherin (liver intestine cadherin). Whether these membrane proteins are good biomarkers in gastric cancer and could refine the significance of CDX2 expression remains unknown. In order to answer these questions, we evaluated the expression of CDX2, GPA33 and LI-cadherin using immunohistochemistry in 350 gastric cancer samples arranged in TMAs (tissue microarrays) and evaluated the co-localization of the biomarkers using fluorescent multiplex immunohistochemistry.
CDX2 was expressed in 36% of the cases, while GPA33 and LI-cadherin were positive in 55% and 66%, respectively. All markers were significantly correlated with each other and are more often expressed in early stage (I and II) cancers (p &lt; 0.05). Overall survival analysis showed that both GPA33 and LI-cadherin predict better outcome. When stratifying the series in early (I and II) and late (III and IV) stages, both proteins significantly associate with better outcome for late stages of disease progression. Overall, these data indicate that the presence of an intestinal differentiation program in gastric cancer is a marker of good prognosis.
The concordance rate between CDX2 and GPA33 and CDX2 and LI-cadherin expression was 68% and 64%, respectively. Since CDX2 displays a heterogeneous pattern of expression and TMA sampling can, by chance, select a negative area in a positive tumour, we also compared CDX2 expression between whole-tissue sections and TMAs. In our series we obtained 68 discrepant cases (positive for CDX2 in whole-tissue sections and negative in the TMAs). For the majority of these cases (50, corresponding to 74%) the combined expression of CDX2 targets, GPA33 and LI-cadherin, can rescue the underrepresentation of CDX2 expression in the TMAs and identifies CDX2-dependent intestinal differentiation.
We conclude that CDX2, GPA33 and LI-cadherin are significantly associated with each other and are commonly expressed in early stages of gastric cancer. The expression of GPA33 and LI-cadherin is associated with better overall survival, particularly in late-stage disease patients. Finally, GPA33 and LI-cadherin are good cell surface surrogate markers for CDX2 expression, not only because of the good concordance of expression, but also because the combined expression of GPA33 and LI-cadherin rescues false negative CDX2 cases in TMAs versus whole-tissue samples.
Citation Format: Nair Lopes, Christian Bergsland, Merete Bjornslett, Jarle Bruun, Ragnhild Lothe, Raquel Almeida, Leonor David. CDX2 targets, GPA33 and LI-cadherin, are novel biomarkers with prognostic value in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 565.