A pan-cancer analysis of the oncogenic function of HMGB1 in human tumors

Our plain-English summary of A pan-cancer analysis of the oncogenic function of HMGB1 in human tumors, by H.M. Yang, X.N. Zhao, X.L. Li, et al (Biochemistry and Biophysics Reports, 2024).

The study

• Authors: H.M. Yang, X.N. Zhao, X.L. Li, X. Wang, Y. Pu, D.K. Wei, Z. Li
• Journal: Biochemistry and Biophysics Reports
• Published: 2024;40:101851
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Although high mobility group box protein 1 (HMGB1) has been researched in relation to cancer in many investigations, a thorough investigation of its role in pan-cancer has yet to be conducted. With the objective of bridging this gap, we delved into the functions of HMGB1 in various tumors.

Methods: This investigation employed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to examine HMGB1 gene expression differences and correlation with survival across various human tumors. Then, genetic alterations of HMGB1 were analyzed by tool cBioPortal, and immune cell infiltration was assessed. Finally, we gathered clinial samples from 95 patients with various types of solid tumor and performed somatic mutation analysis using panel sequencing. This further highlighted the role of HMGB1 in different solid tumors.

Results: There was a notable elevation of HMGB1 gene expression in tumor tissues as opposed to non-cancerous tissues across the bulk of tumor types. Elevated HMGB1 gene expression had a connection with shorter overall survival, progression-free survival, and disease-free survival in specific tumor types. Genetic alterations of HMGB1 suggested that the amplifications and mutations of HMGB1 may impact the prognosis of breast cancer (BRCA) and liver hepatocellular carcinoma (LIHC). Both BRCA and mesothelioma (MESO) displayed a connection between the infiltration of cancer-associated fibroblasts (CAFs) and HMGB1 gene expression. Moreover, HMGB1 co-expression analysis revealed its association with genes involved in RNA splicing, mRNA processing, and modulation of mRNA metabolic processes. Additionally, a pathway analysis by use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) unveiled that HMGB1 was implicated in the pathogenic mechanisms of "Hepatitis B," "Viral Carcinogenesis," and "Hepatocellular Carcinoma." Based on somatic mutation analysis of 95 patients with different solid tumors, we found that the frequency of HMGB1 mutations was higher in Liver cancer patients compared to other solid tumors. This finding is consistent with our in-silico study results. Additionally, we discovered that the frequency of HMGB1 mutations ranked among the top 20 mutated genes in the 95 patients' data, indicating that HMGB1 plays an important role in the development and prognosis of various solid tumors.

Conclusion: This pan-cancer study of HMGB1 underscores its potential as a signature marker and target for the management of various tumor types.

© 2024 The Author(s).

In plain English

This study examined the HMGB1 gene across many cancer types. It mainly used public cancer gene databases. It also sequenced tumors from 95 patients with liver, lung, gastric, colorectal and other cancers. It did not examine asbestos or any exposure. In the main database comparison, HMGB1 expression was higher in tumor than non-cancerous tissue in eleven of 14 cancer types and lower in three. A second comparison found higher expression in four more types. Higher expression was linked to shorter survival in some cancers. Lower expression was linked to shorter survival in others, such as bladder and thyroid cancer. Several reported P values for these links were above 0.05. In mesothelioma (MESO) and some breast and other cancers, HMGB1 expression rose with the estimated level of cancer-associated fibroblasts, a tumor support cell. The text gave no correlation values; results appeared in a figure. Among the 95 patients, HMGB1 changes were most frequent in liver cancer (7 of 12). The authors concluded HMGB1 has potential as a marker and treatment target. They named their limited sample size as a limitation.

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: Bioinformatic (computer-based) analysis of public cancer gene databases, combined with targeted panel sequencing of tumor tissue samples from patients
• Who was studied: Tumor and normal tissue data for many cancer types in public databases (TCGA, GEO, GTEx, CPTAC), plus tissue samples from 95 cancer patients with liver, lung, gastric, colorectal and other cancers. The article does not state where or when the patient samples were collected, beyond approval by the review board of Shuguang Hospital, Shanghai.
• Exposure: No asbestos or other environmental exposure was studied. The factor examined was expression and genetic alteration of the HMGB1 gene.
• Main results:
  • In the initial database comparison of 14 cancer types, HMGB1 gene expression was higher in tumor than in non-cancerous tissue in eleven cancer types. It was lower in lung adenocarcinoma, kidney chromophobe and prostate cancer.
  • Using GTEx non-cancerous tissues as controls, HMGB1 expression was higher in low-grade glioma, diffuse large B-cell lymphoma, thymoma and pancreatic adenocarcinoma (P < 0.05).
  • High HMGB1 expression was reported as correlated with shorter overall survival in ACC, CESE, KICH and LAML (P = 0.007, 0.083, 0.059 and 0.067, respectively). Several of these P values are above 0.05.
  • Low HMGB1 expression was linked to shorter overall survival in BLCA, STAD, THCA and THYM (P = 0.017, 0.0079, 0.0097 and 0.0078).
  • Infiltration (cancer-associated fibroblasts, per the figure legend) was positively correlated with HMGB1 expression in HNSC-HPV, mesothelioma (MESO), BRCA, BRCA-LUMA and TGCT, and negatively correlated in THYM. The text gave no correlation values; the results were presented in Fig. 5 as a heatmap and scatter plot.
  • In TCGA data, the frequency of HMGB1 genetic alterations was highest in DLBC tumor samples (more than 4 %).
  • In colon adenocarcinoma, survival showed no significant difference between cases with and without HMGB1 alterations.
  • In the 95 patient samples, mutations were detected in 84.21 % (80/95) of tumor samples.
  • In the 95 patient samples, HMGB1 genetic alterations were most frequent in liver cancer (58.33 %, 7/12). For comparison, they were 33.33 % (5/15) in lung cancer and 0.00 % (0/4) in breast cancer. HMGB1 was among the top 20 mutated genes.
• The authors' conclusion: The authors concluded that this pan-cancer study points to HMGB1's potential as a signature marker and treatment target for various tumor types. They added that experimental and clinical studies are needed.
• Limitations the authors state:
  • The authors stated that the sample size was constrained.
  • The authors stated that the limited clinical sample size may have biased the comparison of mutation rates between tumor types.
  • The authors stated that the relationship between HMGB1 and liver cancer was not comprehensively explored.

Topics

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Somatic Mutation, Overall Survival, Progression-Free Survival, Disease-Free Survival, Prognosis, Carcinoma, Mesothelioma.

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