An immune-related gene expression signature predicts brain metastasis in lung adenocarcinoma patients after surgery: gene expression profile and immunohistochemical analyses

Koh, Young Wha; Han, Jae‐Ho; Haam, Seok Jin; Lee, Hyun Woo

doi:10.21037/tlcr-20-1056

Cited by 10 publications

(9 citation statements)

References 21 publications

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“…Based on this, we predict that the physical features define largely the types of metastasizing cells can go through the BBBs to reach the internal parts of a brain and the enzymes may define the characteristics of primary cancer cells that survive and thrive in the brain microenvironment. Compared with published studies on prediction of brain metastasis for primary tumors, our model shows higher or comparable accuracy ( 56 , 57 ), but has two key superiorities: (i) the features used in our model are strongly supported by published studies and provide strong information about the key mechanisms of brain metastasis; and (ii) the primary locations of BMPs are not limited to one organ instead any organs, strongly suggesting that our predicted mechanism captures something fundamental.…”

Section: Resultsmentioning

confidence: 58%

Brain metastases: It takes two factors for a primary cancer to metastasize to brain

Liu

Bai²,

Chen³

et al. 2022

Front. Oncol.

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Brain metastasis of a cancer is a malignant disease with high mortality, but the cause and the molecular mechanism remain largely unknown. Using the samples of primary tumors of 22 cancer types in the TCGA database, we have performed a computational study of their transcriptomic data to investigate the drivers of brain metastases at the basic physics and chemistry level. Our main discoveries are: (i) the physical characteristics, namely electric charge, molecular weight, and the hydrophobicity of the extracellular structures of the expressed transmembrane proteins largely affect a primary cancer cell’s ability to cross the blood-brain barrier; and (ii) brain metastasis may require specific functions provided by the activated enzymes in the metastasizing primary cancer cells for survival in the brain micro-environment. Both predictions are supported by published experimental studies. Based on these findings, we have built a classifier to predict if a given primary cancer may have brain metastasis, achieving the accuracy level at AUC = 0.92 on large test sets.

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Section: Resultsmentioning

confidence: 58%

Brain metastases: It takes two factors for a primary cancer to metastasize to brain

Liu

Bai²,

Chen³

et al. 2022

Front. Oncol.

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“…These diseases are those in which ICIs are used more and for a longer time, being the first authorized therapeutic indications shared by the most used ICIs (3,39). In the same way, it should be considered that melanoma and lung cancer patients commonly present brain metastases such as secondary solid tumor (40)(41)(42). So, based on this, the reported brain metastases could also be considered possible therapeutic failure, which today, according to good pharmacovigilance practices (GVP), should be submitted as ICSR when there is at least an associated ADR (43).…”

Section: Discussionmentioning

confidence: 99%

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

et al. 2022

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Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients’ quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as “Neurological disorders NEC” HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile.

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“…Many studies have reported that lung adenocarcinoma, breast cancer, and bladder cancer can significantly produce brain metastasis (13)(14)(15) and cause poor treatment outcomes and poor prognosis (12,14,16). A recent study showed that the gut microbiota can promote the development of glioma (22,24), especially with respect to cell proliferation and tumor invasiveness phenotypes (19)(20)(21).…”

Section: Glioblastomamentioning

confidence: 99%

“…Many studies have shown that metastasis is the most lethal development, especially brain metastasis. Many works have reported that lung adenocarcinoma, breast cancer, and bladder cancer can produce brain metastasis at a significant frequency (12)(13)(14)(15) and cause poor treatment outcomes and poor prognosis (12,14,16). Esophageal cancer can affect intestinal microorganisms (17,18) and indirectly promote the development of GBM, leading to a poor prognosis (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Different Subtypes of Immune Cell Infiltration in Glioblastoma to Aid Immunotherapy

Feng

et al. 2022

Front. Immunol.

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Glioblastoma multiforme (GBM) has been identified as a frequently occurring adult primary brain cancer that is highly aggressive. Currently, the prognostic outcome for GBM patients is dismal, even with intensive treatment, and the median overall survival (OS) is 14.6 months. Immunotherapy, which is specific at the cellular level and can generate persistent immunosurveillance, is now becoming a promising tool to treat diverse cancers. However, the complicated nature of the tumor microenvironment (TME) makes it challenging to develop anti-GBM immunotherapy because several cell types, cytokines, and signaling pathways are involved in generating the immunosuppressive environment. Novel immunotherapies can illustrate novel tumor-induced immunosuppressive mechanisms. Here, we used unsupervised clustering analysis to identify different subtypes of immune cell infiltration that actuated different prognoses, biological actions, and immunotherapy responses. Gene cluster A, with a hot immune cell infiltration phenotype, had high levels of immune-related genes (IRGs), which were associated with immune pathways including the interferon-gamma response and interferon-alpha response, and had low IDH1 and ATRX mutation frequencies. Gene cluster B, a cold immune cell infiltration subtype, exhibited a high expression of the KCNIP2, SCRT1, CPLX2, JPH3, UNC13A, GABRB3, ARPP21, DLGAP1, NRXN1, DLL3, CA10, MAP2, SEZ6L, GRIA2, and GRIA4 genes and a low expression of immune-related genes, i.e., low levels of immune reactivity. Our study highlighted the complex interplay between immune cell infiltration and genetic mutation in the establishment of the tumor immune phenotype. Gene cluster A was identified as an important subtype with a better prognosis and improved immunotherapy response.

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An immune-related gene expression signature predicts brain metastasis in lung adenocarcinoma patients after surgery: gene expression profile and immunohistochemical analyses

Cited by 10 publications

References 21 publications

Brain metastases: It takes two factors for a primary cancer to metastasize to brain

Brain metastases: It takes two factors for a primary cancer to metastasize to brain

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

Characterization of Different Subtypes of Immune Cell Infiltration in Glioblastoma to Aid Immunotherapy

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