HMGB1 overexpression as a prognostic factor for survival in cancer: a meta-analysis and systematic review

Our plain-English summary of HMGB1 overexpression as a prognostic factor for survival in cancer: a meta-analysis and systematic review, by T. Wu, W. Zhang, G. Yang, et al (Oncotarget, 2016).

The study

• Authors: T. Wu, W. Zhang, G. Yang, H. Li, Q. Chen, R. Song, L. Zhao
• Journal: Oncotarget
• Published: 2016;7(31):50417-50427
• Type of article: Meta-analysis, Systematic review
• Cited by: 119 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

As there are millions of cancer deaths every year, it is of great value to identify applicable prognostic biomarkers. As an important alarm, the prognostic role of high mobility group box 1 (HMGB1) in cancer remains controversial. We aim to assess the association of HMGB1 expression with prognosis in cancer patients. Systematic literature searches of PubMed, Embase and Web of Science databases were performed for eligible studies of HMGB1 as prognostic factor in cancer. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the influence of HMGB1 expression on overall survival (OS) and progression-free survival (PFS) in cancer patients. 18 studies involving 11 different tumor types were included in meta-analysis. HMGB1 overexpression was significantly associated with poorer OS (HR: 1.99; 95% CI, 1.71-2.31) and PFS (HR: 2.26; 95% CI, 1.65-3.10) irrespective of cancer types including gastric cancer, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, nasopharyngeal carcinoma, head and neck squamous-cell carcinoma, esophageal cancer, malignant pleural mesothelioma, bladder cancer, prostate cancer, and cervical carcinoma. Subgroup analyses indicated geographical area and size of studies did not affect the prognostic effects of HMGB1 for OS. Morever, HMGB1 overexpression had a consistent correlation with poorer OS when detected by immunohistochemistry in tissues and enzyme-linked immunosorbent assay in serum, whereas the correlation did not exist by quantitative real-time reverse-transcription polymerase chain reaction in tissues. HMGB1 overexpression is associated with poorer prognosis in patients with various types of cancer, suggesting that it is a prognostic factor and potential biomarker for survival in cancer.

In plain English

This article was a systematic review and meta-analysis pooling earlier published studies. The authors searched three databases in September 2015 for studies on whether high HMGB1 (high mobility group box 1) expression, as protein or messenger RNA, predicted cancer survival. They included 18 studies covering 11 cancer types and 2249 participants. Of 17 studies with overall survival data, 15 were from Asia. Across those 17, high HMGB1 was linked to shorter overall survival (hazard ratio 1.99; 95% CI 1.71 to 2.31). Across 7 studies it was linked to shorter progression-free survival (hazard ratio 2.26; 95% CI 1.65 to 3.10). Malignant pleural mesothelioma appeared in a single Japanese study measuring HMGB1 in serum (hazard ratio 2.10; 95% CI 1.00 to 4.40). In two studies using a gene-activity test (qRT-PCR) on tissue, no statistically significant link with overall survival was found (hazard ratio 2.71; 95% CI 0.73 to 10.02). The article does not discuss asbestos. The authors concluded that HMGB1 overexpression is associated with poorer prognosis and may be a prognostic biomarker. They noted mixed measurement methods and a bias toward Asian patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review and meta-analysis of published prognostic studies (15 prospective and 3 retrospective cohorts)
• Who was studied: 18 published studies covering 11 cancer types and 2249 participants in total: 2090 in the overall survival analyses and 1247 in the progression-free survival analyses. Of the 17 overall survival studies, 15 were from Asia (11 China, 3 Japan, 1 Korea) and 2 from Europe. One included study (Tabata et al, Japan, 2005-2009) concerned malignant pleural mesothelioma.
• Exposure: Not an asbestos exposure. The factor studied was high (over-) expression of HMGB1, measured as mRNA or protein in tissue or serum. In the overall survival studies, it was measured by immunohistochemistry in tumor tissue (11 studies), by qRT-PCR in tumor tissue (2 studies), or by ELISA in blood serum (4 studies).
• Main results:
  • All cancers pooled (17 studies): HMGB1 overexpression was associated with poorer overall survival, HR 1.99 (95% CI 1.71-2.31).
  • All cancers pooled (7 studies): HMGB1 overexpression was associated with shorter progression-free survival, HR 2.26 (95% CI 1.65-3.10).
  • Malignant pleural mesothelioma (one study, serum ELISA): overall survival HR 2.10 (95% CI 1.00-4.40) for high versus low HMGB1. The lower limit of the interval is 1.00.
  • When HMGB1 was measured by qRT-PCR in tissue (2 studies), the association with overall survival was not statistically significant: HR 2.71, with a wide 95% CI of 0.73-10.02. The authors described this as no correlation.
  • When HMGB1 was measured by ELISA in serum (4 studies), it was associated with poorer overall survival, HR 2.32 (95% CI 1.59-3.40).
  • By region, overall survival was shorter with high HMGB1 in studies from Asia (HR 1.94; 95% CI 1.67-2.26) and in studies from Europe (HR 2.93; 95% CI 1.58-5.43).
  • By study size, overall survival hazard ratios were similar for studies with fewer than 100 patients (HR 2.06; 95% CI 1.57-2.69) and studies with 100 or more patients (HR 1.96; 95% CI 1.64-2.34).
• The authors' conclusion: The authors concluded that HMGB1 overexpression is associated with poorer overall and progression-free survival in various cancers, suggesting it is a prognostic factor and potential biomarker for survival.
• Limitations the authors state:
  • The included studies used different specimen sources and detection methods.
  • There is no internationally accepted, validated method for measuring HMGB1.
  • The authors said the limited number and small size of the available qRT-PCR studies may explain the non-significant result for that method.
  • In 2 studies the hazard ratios came from univariate analysis, because no multivariate analysis was done.
  • The data were biased toward Asian patients.
  • None of the included studies mentioned important confounders such as subsequent treatment.
  • The authors stated that the findings need confirmation by future studies.

Topics

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Meta-Analysis, Systematic Review, Biomarker, Prognosis, Hazard Ratio, confidence interval, Overall Survival.

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• Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma — C. Tabata, E. Shibata, et al. (2013)
• HMGB1 as a Potential Biomarker and Therapeutic Target for Malignant Mesothelioma — Y. Wang, Z. Jiang, et al. (2019)
• Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases — S. Ying, Z. Jiang, et al. (2017)
• HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients — A. Napolitano, D.J. Antoine, et al. (2016)

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