B7-H3 and PD-L1 Expression Are Prognostic Biomarkers in a Multi-racial Cohort of Patients with Colorectal Cancer

Zhang, Wei; Acuña-Villaorduña, Ana; Kuan, Kevin; Gupta, Sorab; Hu, Shaomin; Ohaegbulam, Kim C.; Albanese, Joseph; Kaumaya, Meghan; Levy, Rachel; Hwang, Richard; Zang, Xingxing; Lin, Juan; Liu, Qiang; Maitra, Radhashree; Goel, Sanjay

doi:10.1016/j.clcc.2021.02.002

Cited by 18 publications

(24 citation statements)

References 28 publications

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“…Experimental studies in mice showed that induction of colitis and water avoidance stress affect levels of Mir29a and Mir29b and intestinal permeability in wildtype mice (71). Despite inconsistent results and conflicting conclusions of existing prognostic studies of B7-H3 (22,(24)(25)(26)(27)(28)(29)(30)(32)(33)(34)(35)(36)(37), our study, with the largest sample size, confirmed that it was a significant and independent biomarker to colon cancer survival by several trans-ethnical validations.…”

Section: Discussionsupporting

confidence: 63%

“…An array of studies have indicated that highly expressed B7-H3 promotes tumor progression and metastasis, as well as being associated with poor prognosis in various of cancers, including glioma (15), hepatocellular carcinoma (16), lung cancer (17), breast cancer (18), osteosarcoma (19), cutaneous melanoma (20), and pancreatic cancer (21). However, the results of existing prognostic studies of B7-H3 expression and colon cancer (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) have been inconsistent and have presented conflicting conclusions; thus, we believe there is an urgent need to elaborate the effect of B7-H3 on colon cancer survival. Besides, various technical bottlenecks of previous studies need to be addressed: (I) there have been very few European studies (22,23,29), and majority of these studies were conducted among Asian populations (24)(25)(26)(27)(28)(30)(31)(32)(33)(34)(35)(36)(37); (II) no study so far has focused on the non-linear effects of B7-H3 on colon cancer survival, with previous studies simply having tested its linear effect; (III) there has been no independent validation of B7-H3, the association has consistently been evaluated in a single population; and (IV) there have been no trans-ethnic population studies of B7-H3 thus far.…”

Section: Introductionmentioning

confidence: 99%

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A three-phase trans-ethnic study reveals B7-H3 expression is a significant and independent biomarker associated with colon cancer overall survival

Gao¹,

Xu²,

Gao³

et al. 2021

J Gastrointest Oncol

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Background: There have been inconsistent results and conflicting conclusions among the existing prognostic studies of B7-H3 expression in colon cancer patients. Therefore, the association between B7-H3 expression and colon cancer survival has remained largely unclear.Methods: We performed a three-phase and trans-ethnic prognostic study of B7-H3 expression in colon cancer patients involving perhaps the largest population to date. In the discovery phase, we utilized a Cox proportional hazards model adjusted for covariates to test the association between B7-H3 expression and colon cancer overall survival (OS) time in a European population from The Cancer Genome Atlas (TCGA) cohort (n=433). In the validation phase I, the association was replicated in a European population from Gene Expression Omnibus (GEO) cohort (n=811). In the validation phase II, we again confirmed the significant association in an Asian population from Fujian Medical University Union Hospital (UNION) cohort (n=179).Furthermore, a series of Kaplan-Meier analysis, bioinformatics analysis of tumor immune microenvironment (TIME), and immune checkpoint prognostic prediction analysis, as well as sensitivity analysis, were also conducted.Results: Highly expressed B7-H3 was a significant and robust biomarker to colon cancer survival, with a large hazard ratio (HR) [HR TCGA =4.60, 95% confidence interval (CI): 2.15 to 9.83, P=8.37×10 −05 ; HR GEO =1.47, 95% CI: 1.12 to 1.94, P=0.0056; HR UNION =1.63, 95% CI: 1.36 to 1.95, P=7.91×10 −08 ]. We detected an involvement of B7-H3 in the tumor immune microenvironment (TIME). Meanwhile, B7-H3 was significantly and weakly correlated with 6 out of 27 well-recognized immune checkpoint genes. Even after adjusting for effects of other immune checkpoint genes, B7-H3 still exhibited a harmful effect on colon cancer survival using samples from TCGA and GEO cohorts (HR =1.47, 95% CI: 1.07 to 2.02, P=0.0184), indicating that it was an independent prognostic factor of colon cancer. We also proposed an immune checkpoint prognostic risk score which possessed the capability to identify colon cancers with high risk of mortality. Conclusions:The expression of B7-H3 is a significant, robust, and independent prognostic factor to colon cancer OS.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

A three-phase trans-ethnic study reveals B7-H3 expression is a significant and independent biomarker associated with colon cancer overall survival

Gao¹,

Xu²,

Gao³

et al. 2021

J Gastrointest Oncol

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show abstract

“…Janakiram et al [ 9 ] demonstrated that HHLA2 is widely expressed in a large proportion of cancer samples such as breast cancer, colon cancer, and prostate cancer. In recent years, studies have shown that HHLA2 participates in the growth and development of a variety of cancers [ 7 , 10 , 11 ]. However, to date, the expression pattern, prognostic significance, and biological function of HHLA2 in cancer have not been elucidated fully.…”

Section: Introductionmentioning

confidence: 99%

[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

Yang

et al. 2022

BioMed Research International

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Background. The role of HERV–H LTR-associating 2 (HHLA2) in cancer remains still unclear. This study analyzed the correlation between the prognosis and immune infiltrate function of HHLA2 in pan-cancers. Methods. HHLA2 expression in pan-cancers was analyzed using the databases of TCGA, GTEx, TIMER, GEPIA, UALCAN, and GSEA databases. Multiple bioinformatic methods were used to investigate the correlation of HHLA2 expression with survival, pathological stage, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune cell infiltration, and immune checkpoint gene (ICG), and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Results. HHLA2 was aberrantly expressed and was strongly correlated with positive or negative prognosis in multiple human cancers, which revealed that HHLA2 might play a vital role during cancer formation and development. Kaplan–Meier (KM) curves across cancers revealed that HHLA2 expression was correlated with overall survival (OS) in eight cancers, disease-specific survival (DSS) in seven cancers, disease-free interval (DFI) in four cancers, and progression-free interval (PFI) in nine cancers. Furthermore, HHLA2 expression was positively correlated with TMB in 6 cancer types and negatively associated with TMB in 7 cancer types, respectively. The former included ESCA, HNSC, KIRP, PAAD, PRAD, and PCPG; the latter contained COAD, LGG, LUAD, LUSC, THYM, THCA, and UCEC. Additionally, we found HHLA2 expression was negatively related to MSI in ACC, COAD, PAAD, and UCEC. More importantly, HHLA2 expression was remarkably correlated with the degree of tumor-infiltrating immune in many cancers, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells and strongly associated with immune checkpoint genes in 13 tumor types. Furthermore, KEGG pathway analyses indicated that HHLA2 could potentially impact cancer etiology or pathogenesis by functioning in amino sugar and nucleotide sugar metabolism, cytosolic DNA sensing pathway, and peroxisome pathways. Meanwhile, GSVA analysis results all indicate that HHLA2 was correlated with TSC/mTOR, RTK, RAS/MAPK, PI3K/AKT, EMT, DNA Damage Response, Cell Cycle, and Apoptosis pathways in various cancers. Conclusion. HHLA2 can function as a prognostic biomarker and correlate with tumor immunity in human pan-cancer due to its important role in tumorigenesis and immune infiltration, which provides new insight into developing new targeted treatments in cancers.

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“…Overexpressed in multiple human cancer types, the prognostic role of HHLA2 remains controversial ( Table 1 ). Several studies indicated that overexpression of HHLA2 in tumour cells was associated with unfavorable clinical outcomes and shorter survival rate in patients with prostate cancer, 26 neuroendocrine tumours, 27 hepatocellular carcinoma, 28 , 29 , 30 lung adenocarcinoma, 31 , 32 , 33 , 34 gastric cancer, 35 oral squamous cell carcinoma, 36 bladder urothelial carcinoma, 37 intrahepatic cholangiocarcinoma, 38 colorectal carcinoma, 39 , 40 osteosarcoma, 41 and triple negative breast cancer. 17 On the contrary, HHLA2 was a protective factor predicting low mortality rate in patients with pancreatic cancer, 14 , 42 , 43 epithelial ovarian cancer, 44 malignant glioma, 45 and recurrent or unresectable advanced gastric cancer.…”

Section: Role Of Hhla2 In Cancer Developmentmentioning

confidence: 99%

“… Prostate cancer 2021 Patient tumour samples, N = 239 Tumour cells High HHLA2 expression was an independent prognostic predictor for prostate cancer, and was negatively correlated with CD

TILs 26 Neuroendocrine tumours 2021 Patient tumour samples, N = 37 Tumour cells High HHLA2 expression was correlated with high tumour grade and metastasis 27 Colorectal cancer 2021 Patient tumour samples, N = 214 Tumour cells HHLA2 expression was low in colorectral cancer and appeared to have no influence on clinical outcomes. 40 Hepatocellular carcinoma 2021 Patient tumour samples, N = 205 Peri-tumour region of HCC tissues HHLA2 expression in the peri‑tumour region was an independent prognostic factor for OS, and was negatively correlated with PD-L1 28 Patient tumour samples, N = 55 Tumour cells Higher expression of HHLA2 protein was associated with advanced cancer stage, tumour differentiation, and invasion of adjacent structures 29 Patient tumour samples, N = 202 Tumour cells HHLA2 level was a independent worse prognostic factor and affected the tumour microenvironment 30 Epithelial ovarian cancer 2021 Patient tumour samples, N = 64 Tumour cells HHLA2 was correlated with high CD

TIL levels and tumour differentiation; and predicted improved survival in ovarian cancer 44 Lung adenocarcinoma 2021 Patient tumour samples, N = 62 Tumour cells HHLA2 expression was an prognostic factor for PFS, and was positively correlated with EGFR overexpression …”

Section: Role Of Hhla2 In Cancer Developmentmentioning

confidence: 99%

Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy

Ying

Zhang

et al. 2022

eBioMedicine

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B7-H3 and PD-L1 Expression Are Prognostic Biomarkers in a Multi-racial Cohort of Patients with Colorectal Cancer

Cited by 18 publications

References 28 publications

A three-phase trans-ethnic study reveals B7-H3 expression is a significant and independent biomarker associated with colon cancer overall survival

A three-phase trans-ethnic study reveals B7-H3 expression is a significant and independent biomarker associated with colon cancer overall survival

[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy

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