Insights into the molecular alterations of PLAG1 and HMGA2 associated with malignant phenotype acquisition in pleomorphic adenoma

Pleomorphic adenoma (PA) is the most common neoplasm of the salivary gland, presenting with a variety of histological features. In some cases, PA can undergo malignant transformation to carcinoma ex pleomorphic adenoma (CXPA). The transition from PA to CXPA is associated with complex molecular alterations, particularly involving the pleomorphic adenoma gene 1 (PLAG1) and high mobility group protein gene (HMGA2). This review investigates the molecular alterations of PLAG1 and HMGA2 in all domains in the malignant transformation of PA. Our analysis highlights that these markers are key alterations in the etiopathogenesis of PA and CXPA, with gene fusion and amplification being frequently reported mechanisms. Although the exact role of PLAG1 and HMGA2 in the oncogenic process remains unclear, further studies on the HMGA2 and PLAG1, are needed particularly in HMGA2-PLAG1-IGF2 which is proving to be a potential pathway for the development of clinically applicable therapies, especially for CXPA management.