Prevalence and Significance of HMGA2 Expression in Esophageal Adenocarcinoma

Abstract

Aims

Esophageal adenocarcinoma (EAC) tumorigenesis has been primarily linked to loss-of-function mutations in tumor suppressor genes. Knowledge of specific oncogenes that drive tumor progression, and their relationship to outcomes, is limited. High Mobility Group AT-Hook 2 (HMGA2) has been reported to be amplified in a subset of EACs, but the clinicopathologic and prognostic implications of HMGA2 expression in EAC is unknown.

Methods and Results

We performed HMGA2 immunohistochemistry and fluorescence in-situ hybridization (FISH) in EAC to determine its clinicopathologic and prognostic significance. Ninety-one primary EAC resections without neoadjuvant treatment were identified and immunohistochemistry for HMGA2 was performed. The presence or absence of nuclear staining was evaluated and correlated with predetermined clinicopathologic parameters and patient outcomes. A selected subset of tumors was subjected to FISH to identify alterations at the HMGA2 locus. HMGA2 expression was present in 25/91 (27.4%) tumors. HMGA2 expressing cells were present in solid, poorly differentiated areas of the tumors at the invasive front, or as single infiltrating cells. FISH showed that 3-4 copies of HMGA2 are frequently present in EAC irrespective of HMGA2 protein expression and that high level HMGA2 amplification is a rare event. HMGA2 expression was associated with numerous adverse clinicopathologic parameters including higher T- and N-stage, the presence of lymphovascular invasion, and with a worse recurrence free and overall survival.

Conclusion

Our data suggests that HMGA2 is primarily regulated in EAC through non-chromosomal level alterations that lead to increased HMGA2 expression. HMGA2 positive EAC correlates with adverse pathologic features and worse patient outcomes.

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