Prognostic Implications of the Complement Protein C1q in Gliomas

Our plain-English summary of Prognostic Implications of the Complement Protein C1q in Gliomas, by A. Mangogna, B. Belmonte, C. Agostinis, et al (Frontiers in Immunology, 2019).

The study

• Authors: A. Mangogna, B. Belmonte, C. Agostinis, P. Zacchi, D.G. Iacopino, A. Martorana, V. Rodolico, D. Bonazza, F. Zanconati, U. Kishore, R. Bulla
• Journal: Frontiers in Immunology
• Published: 2019;10:2366
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The contribution of the complement system in the pathophysiology of brain cancers has been recently considered in light of its well-known involvement in carcinogenesis. Complement system represents an important component of the inflammatory response, which acts as a functional bridge between the innate and adaptive immune response. C1q, the first recognition subcomponent of the complement classical pathway, has recently been shown to be involved in a range of pathophysiological functions that are not dependent on complement activation. C1q is expressed in the microenvironment of various types of human tumors, including melanoma, prostate, mesothelioma, and ovarian cancers, where it can exert a protective or a harmful effect on cancer progression. Despite local synthesis of C1q in the central nervous system, the involvement of C1q in glioma pathogenesis has been poorly investigated. We, therefore, performed a bioinformatics analysis, using Oncomine dataset and UALCAN database in order to assess whether the expression of the genes encoding for the three chains of C1q (C1qA, C1qB, and C1qC) could serve as a potential prognostic marker for gliomas. The obtained results were then validated using an independent glioma cohort from the Chinese Glioma Genome Atlas datasets. Our bioinformatics analysis, coupled with immunohistochemistry and fluorescence microscopy, appears to suggest a positive correlation between higher levels of C1q expression and unfavorable prognosis in a diverse grade of gliomas.

Copyright © 2019 Mangogna, Belmonte, Agostinis, Zacchi, Iacopino, Martorana, Rodolico, Bonazza, Zanconati, Kishore and Bulla.

In plain English

This study is about gliomas (brain tumors), not asbestos. Mesothelioma appears only in background describing other research. The authors used public gene-activity databases (Oncomine, UALCAN drawing on The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas) to ask whether activity of the three genes for the complement protein C1q (C1qA, C1qB, C1qC) was linked to survival. They also stained tumor tissue from five patients per glioma grade in Trieste, Italy. Across several datasets, C1q gene activity was significantly higher in gliomas than in normal brain. In the TCGA data, higher activity went with poorer survival in low-grade gliomas (grades II and III) but not in glioblastoma (grade IV). In the Chinese data, it went with poorer survival in all grades combined, in grade III and in glioblastoma, but not in grade II. Tumor tissue contained abundant C1q, mainly in macrophages, with no sign of complement activation. The authors noted that their finding of no complement activation was based on tissue samples from five patients. They concluded that further investigation is needed before C1q could be used as a prognostic marker.

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: Bioinformatics analysis of public gene-expression databases, with immunohistochemistry and fluorescence microscopy on glioma tissue samples
• Who was studied: Glioma and normal brain samples in public datasets: the Oncomine datasets (Sun, French, TCGA, Rickman, Bredel 2, Liang), TCGA data via UALCAN, and the Chinese Glioma Genome Atlas RNA dataset of 325 samples (109 grade II, 72 grade III, 144 grade IV). Also glioma tissue from five patients for each glioma grade at the University Hospital of Cattinara, Trieste, Italy
• Exposure: No asbestos or other exposure was studied. The factor examined was expression of the genes for the three chains of the complement protein C1q (C1qA, C1qB, C1qC), and C1q protein in tumor tissue
• Main results:
  • In the Oncomine datasets, mRNA levels of C1qA, C1qB and C1qC were significantly higher in gliomas of different types and grades than in normal brain tissue (P less than 0.05)
  • In the UALCAN analysis of TCGA data, higher expression of the three C1q chains correlated with unfavorable prognosis only in low-grade gliomas (grades II and III), with reduced survival probability (P less than 0.05)
  • In the UALCAN analysis of TCGA data, no correlation was found between C1q chain expression and survival probability in glioblastoma (grade IV)
  • In the Chinese Glioma Genome Atlas data, higher expression of the three C1q chains correlated with unfavorable prognosis across all WHO grades of glioma (P less than 0.05)
  • In the Chinese Glioma Genome Atlas data, a similar unfavorable prognostic effect was found in grade III gliomas (P less than 0.05), with no correlation in grade II gliomas
  • In the Chinese Glioma Genome Atlas data, unlike the UALCAN analysis, a negative prognostic effect was seen in glioblastoma (P less than 0.05)
  • In the tissue samples, C1q protein was highly expressed in both low-grade gliomas and glioblastoma
  • No C3d or C4d staining (markers of complement activation) was found in the glioma specimens
  • C1q co-localized with the macrophage marker CD68 in low- and high-grade gliomas, and most C1q-labeled cells co-localized with CD163, a marker of M2-polarized macrophages
• The authors' conclusion: The authors concluded that C1q plays a fundamental role in the pathogenesis of gliomas, but that further investigation is required before it can be used in the clinic as a prognostic marker
• Limitations the authors state:
  • The authors stated that the absence of C3d and C4d (no complement activation) was found in a cohort of tumor specimens with n = 5, and that their conclusions were based on only five patients' tissue samples subjected to immunohistochemistry. The methods, however, describe five patients for each glioma grade
  • The bioinformatics analysis was based solely on mRNA expression data and requires validation at the protein level
  • Neither dataset distinguished de novo (primary) from secondary glioblastoma, which may have masked a correlation
  • The glioblastoma results conflicted between the two datasets. The authors suggested this may reflect the algorithms used to define high and low expression, or genetic differences between the mostly Caucasian TCGA patients and the Chinese CGGA cohorts

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Mesothelioma, Ovarian Cancer, Immunohistochemistry, Prognosis.

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