FOG1: A Highly Sensitive and Specific Diagnostic Marker for Gastroesophageal Adenocarcinoma

Currently, there is no sensitive and specific diagnostic immunohistochemistry (IHC) marker to identify gastric and esophageal adenocarcinomas (GEAs). CDX2 is the most widely used tumor marker to determine gastrointestinal (GI) origin and has been shown to be an excellent marker for lower GI adenocarcinomas, including both small and large bowel adenocarcinomas. However, it has limited utility in upper GI adenocarcinomas, as CDX2 is a key marker for intestinal differentiation and is expressed in fewer than 50% of all gastric adenocarcinomas. In this study, through TCGA data mining, we identified friend of GATA1 (FOG1) as a potential sensitive and specific marker for GEAs, as high mRNA expression levels of FOG1 were found exclusively in GEAs across 29 solid tumor types. We then analyzed FOG1 and CDX2 protein expressions by IHC in 187 cases of GEA and esophageal squamous cell carcinomas (eSCC) and found that neither FOG1 nor CDX2 was expressed in eSCC. In contrast, the majority (91.1%) of GEAs showed moderate to high FOG1 expression, whereas 51.3% of GEAs demonstrated negative to low CDX2 expression. Only 4 (2.5%) GEAs showed moderate to high CDX2 expression with negative to low FOG1 expression. Conversely, among 168 cases of colonic adenocarcinoma, most (71.4%) exhibited intermediate-to-high CDX2 expression, whereas 92.9% showed negative-to-low FOG1 expression. Only 5 (3%) colonic adenocarcinomas demonstrated moderate-to-high FOG1 expression with negative-to-low CDX2 expression. Moderate to high FOG1 expression was detected in a small proportion of pancreatic (15.5%) and ampullary (11.2%) adenocarcinomas, but was rare (1.6% to 3.3%) in adenocarcinomas of the breast, lung, and ovary. In addition, there were no FOG1 expressions detected in lung squamous cell carcinoma, hepatocellular carcinoma, melanoma, and carcinomas of the salivary gland, thyroid, bladder, kidney, prostate, and uterus. Our data indicate that FOG1 is not only a sensitive, but also a specific marker for gastroesophageal adenocarcinoma.