HMGB1 overexpression is a strong and independent prognostic feature in ERG negative prostate cancer

High-mobility group box 1 (HMGB1) is a chromatin-associated protein with a key role in DNA damage repair and genome stability, involved in DNA replication, transcription, and chromatin remodeling. By impacting the activity of multiple signaling pathways HMGB1 contributes to critical characteristics of cancer cells including proliferation, migration and invasion, angiogenesis, and cellular energy metabolism. Depending on the tumor type, both increased and reduced expression of HMGB1 have been found to be linked to unfavorable tumor features and poor patient prognosis. To better understand the prevalence and clinical relevance of HMGB1 expression in prostate cancer, a tissue microarray containing 17,747 prostate cancer samples from patients with follow-up data was analyzed by immunohistochemistry (IHC). In normal prostate epithelium, HMGB1 expression was strong in basal cells but only weak in acinar cells which are considered the precursor cells of prostatic adenocarcinoma. HMGB1 IHC was interpretable in 13,642 cancers and was rated negative in 19.9%, weak in 56.1%, moderate in 22.4%, and strong in 1.6% of tumors. HMGB1 staining was significantly more frequent and more intense in cancers harboring the TMPRSS2:ERG fusion (91.6% positive) than in ERG fusion negative tumors (70.4% positive; p<0.0001). A comparison with clinico-pathological features revealed significant associations between high HMGB1 expression and advanced pT stage, high Gleason grade, high quantitative Gleason grade (p≤0.0001 each), nodal metastases (p=0.0038), and early PSA recurrence (p<0.0001). A subgroup analysis of 3,854 ERG positive and 4,751 ERG negative cancers revealed that the prognostic impact of HMGB1 expression was entirely driven by the ERG negative group (p<0.0001) while the level of HMGB1 expression did not impact PSA recurrence in ERG positive cancers. Several different multivariate analyses considering either preoperatively available (cT, PSA, Gleason grade obtained on biopsies) or postoperatively available (pT, pN, Gleason grade obtained on the entire prostate, R status) parameters unanimously revealed an independent prognostic impact of HMGB1 expression in ERG negative cancers (p<0.0001) if compared to established prognostic parameters. It is concluded that HMGB1 overexpression is a potentially clinically useful prognostic feature of ERG negative prostate cancer which can be assessed by IHC. The striking impact of the ERG status on the prognostic role of HMGB1 expression could be identified due to high dimension of our patient cohort. It may be possible that other molecular key alterations also critically affect the impact of established prognostic markers in other cancer types.