High expression of HHLA2 predicts poor prognosis in medullary thyroid carcinoma

Abstract

Background: Human endogenous retrovirus-H long terminal repeat-associating protein 2 is a newly identified immune checkpoint molecule that was aberrantly expressed in many malignant tumors. However, its expression in medullary thyroid carcinoma is still unclear. This study aimed to investigate the human endogenous retrovirus-H long terminal repeat-associating protein 2 expression in medullary thyroid carcinoma tissues and to evaluate the relationships between its expression and clinicopathologic together with prognostic relevance.

Methods: Using 51 surgical specimens obtained from medullary thyroid carcinoma patients, the expression levels of the human endogenous retrovirus-H long terminal repeat-associating protein 2 protein in medullary thyroid carcinoma tumor tissues and adjacent noncancerous tissues were measured by immunohistochemistry, and its correlations with clinicopathologic and prognostic features were analyzed. Status of CD8+ tumor infiltrating lymphocytes was also investigated.

Results: The results showed that human endogenous retrovirus-H long terminal repeat-associating protein 2 was only detected in tumor tissues, and 31.4% of the medullary thyroid carcinoma patients had high expression of human endogenous retrovirus-H long terminal repeat-associating protein 2. High human endogenous retrovirus-H long terminal repeat-associating protein 2 expression was significantly associated with lymph node metastasis and advanced American Joint Committee on Cancer stages (P = 0.005). There existed an inverse trend between human endogenous retrovirus-H long terminal repeat-associating protein 2 expression and CD8+ tumor infiltrating lymphocytes infiltration in medullary thyroid carcinoma tumor samples (P = 0.042). The log-rank test showed a shorter disease-free survival in patients with high human endogenous retrovirus-H long terminal repeat-associating protein 2 expression (P = 0.002). The disease-free survival rates were also significantly low in cases of medullary thyroid carcinoma with lymph node metastasis, American Joint Committee on Cancer stages III-IV and multifocality. Multivariate Cox analysis confirmed that human endogenous retrovirus-H long terminal repeat-associating protein 2 acted as an independent predictive factor in the disease-free survival of medullary thyroid carcinoma patients (hazard ratio = 4.138, 95% confidence interval: 1.027-16.667, P = 0.046).

Conclusions: Taken together, human endogenous retrovirus-H long terminal repeat-associating protein 2 is highly expressed in medullary thyroid carcinoma patients and is a poor prognostic biomarker of disease-free survival of medullary thyroid carcinoma patients.

Keywords: HHLA2; biomarker; medullary thyroid carcinoma; prognosis.