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To investigate HMGA2\u2019s role in cancer, a tissue microarray of 18,582 samples from 154 tumor types and 608 samples from 76 normal tissues was analyzed. HMGA2 expression was generally higher in cancer than in normal tissues. Of the 15,915 tumor samples, 37.5% showed HMGA2 positivity: 12% weak, 11.5% moderate, and 13.9% strong. HMGA2 was detected in at least one case in 118 of 144 tumor categories, with strong staining in 92 categories. The frequency of HMGA2 positivity was highest in cancers of the ovary and the endometrium (52.6\u201392.6%), thyroidal neoplasms (53.4\u201395%), salivary gland neoplasms (66.7\u201398%), and non-seminomatous testicular germ cell tumors (73.5\u201393.5%). High-level HMGA2 staining was associated with invasive tumor growth of urinary bladder cancers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001); high-grade, advanced pT, metastasis, and poor overall survival (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001 each) in clear cell renal cell carcinoma (RCC); nodal metastasis in papillary RCC (<jats:italic>p<\/jats:italic>\u2009=\u20090.0099); as well as nodal metastasis in papillary thyroid cancer (<jats:italic>p<\/jats:italic>\u2009=\u20090.0063). Low HMGA2 expression was linked to microsatellite instability in colorectal cancer (<jats:italic>p<\/jats:italic>\u2009=\u20090.0002) and HPV infection in squamous cell carcinomas (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). It is concluded that HMGA2 is highly expressed in a very broad range of tumor entities. These findings emphasize a potential role of HMGA2 as a drug target and suggest utility for HMGA2 IHC for the distinction of neoplastic from non-neoplastic tissues in several organs.<\/jats:p>","DOI":"10.1007\/s00428-025-04142-1","type":"journal-article","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T20:24:52Z","timestamp":1750019092000},"page":"183-201","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["High mobility group protein 2 (HMGA2) is highly expressed in a broad range of benign and malignant tumors"],"prefix":"10.1007","volume":"487","author":[{"given":"Viktoria","family":"Chirico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih 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