Abstract 99: HMGB1deficiency occurs in a broad range of human cancers and is often associated with unfavorable tumor phenotype

Abstract High-mobility group protein B1 (HMGB1) is a chromatin-associated protein with a role in maintenance of nucleosome structure, transcription control, and DNA repair. Both its overexpression and impaired function have been linked cancer development and progression. To better comprehend the role of HMGB1 expression in cancer, a tissue microarray containing 14, 966 samples from 134 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. A strong nuclear HMGB1 staining occurred in almost all normal cell types and in most cancers. Of 11, 808 evaluable cancers, only 921 (7.8%) showed a complete HMGB1 expression loss (HMGB1 deficiency) while 1, 172 (9.9%) showed a 1+, 2, 956 (25%) showed a 2+, and 6, 759 (57.2%) showed a 3+ HMGB1 positivity. HMGB1 deficiency most frequently occurred in pheochromocytoma (90%), seminoma (72.4%), gastrointestinal stromal tumor (28.6%), adrenal cortical carcinoma (25%), and Hodgkin's lymphoma (25%). Low HMGB1 expression was linked to poor histologic grade (p<0.0001), advanced pT stage (p<0.0001), high UICC stage (p<0.0001), and distant metastasis (p=0.0413) in clear cell RCC, invasive tumor growth in urothelial carcinoma (pTa vs. pT2-4, p<0.0001), mismatch repair deficiency (p=0.0167) in colorectal cancers, and advanced pT stage in breast cancer of no special type (NST) (p=0.0038). High HMGB1 expression was linked to nodal metastases in high-grade serous ovarian carcinomas (p=0.0213) and colorectal cancers (p=0.0137), as well as to high histological grade in squamous cell carcinomas (p=0.001). In conclusion, our data show that HMGB1 deficiency and reduced HMGB1 expression occurs in a broad range of different tumor entities and that low (and not high) HMGB1 expression is often linked to an aggressive tumor phenotype. Whether or not HMGB1 deficiency renders cells susceptible to specific drugs remains to be determined. Citation Format: Viktoria Chirico, Hena Sharifi, Maria Christina Tsourlakis, Seyma Büyücek, Clara von Bargen, Katharina Möller, Florian Lutz, David Dum, Claudia Hube-Magg, Elena Bady, Lisa Hornsteiner, Georgia Makrypidi-Fraune, Piero Caneve, Maximilian Lennartz, Morton Freytag, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Eike Burandt, Till S Clauditz, Patrick Lebok, Christoph Fraune, Till Krech, Sarah Minner, Andreas H Marx, Waldemar Wilczak, Ronald Simon, Guido Sauter, Stefan Steurer, Kristina Jansen. HMGB1deficiency occurs in a broad range of human cancers and is often associated with unfavorable tumor phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 99.