Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia

Djulbegovic, Mak; Uversky, Vladimir N.; Karp, Carol L.; Harbour, J. William

doi:10.1016/j.ijbiomac.2021.11.120

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…46 TTN mutations were also more common in CD8T-RGPI high-risk samples, and are associated with chromosomal instability and oncogenesis. 47 Therefore, the CD8T-RGPI high-risk patients with high TP53 and TTN mutations exhibited worse outcomes, relative to CD8T-RGPI low-risk patients with low TP53 and TTN mutations, in agreement with our survival findings.…”

Section: Discussionsupporting

confidence: 89%

“…TP53 mutations can significantly increase incidences of malignant tumours in patients, presenting as more aggressive diseases with poorer patient outcomes, 44,45 especially in HCC 46 . TTN mutations were also more common in CD8T‐RGPI high‐risk samples, and are associated with chromosomal instability and oncogenesis 47 . Therefore, the CD8T‐RGPI high‐risk patients with high TP53 and TTN mutations exhibited worse outcomes, relative to CD8T‐RGPI low‐risk patients with low TP53 and TTN mutations, in agreement with our survival findings.…”

Section: Discussionmentioning

confidence: 99%

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A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients

et al. 2022

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Immune checkpoint blockade (ICB) therapy is a promising treatment for hepatocellular carcinoma (HCC). However, it is limited by low response rates. Tumour‐infiltrating immune cells (TIICs), specifically CD8+ T cells, in the tumour microenvironment (TME) are related to tumour immune responses and are potential predictors for immunotherapeutic and survival outcomes. Therefore, we established a new CD8+ T cell‐related genes prognostic index (CD8T‐RGPI) for evaluating immune responses and prognostic outcomes for HCC. Using the TCGA databases, we evaluated the RNA‐seq data of CD8+ T cell‐related genes with gene co‐expression network. Then, the CD8T‐RGPI model was built by combining univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The nomogram exhibited a good prediction ability for HCC patients' prognosis in either TCGA or ICGC databases. The CD8T‐RGPI was elevated in patients with high T, M and TNM stages. Functional enrichment analyses revealed that in CD8T‐RGPI high‐risk group, tumour‐related and immunosuppressive pathways, such as focal adhesion, aerobic glycolysis, HIF1 transcription factor pathway, IL‐4 and IL‐13 signalling were significantly enriched. Moreover, for CD8T‐RGPI high‐risk HCC patients, immune tolerance and immunosurveillance escape was associated with poor therapeutic outcomes for ICB therapy. The CD8T‐RGPI low‐risk HCC patients with elevated immune infiltration levels were associated with good immunotherapeutic responses to ICB. Our findings provide prospective prognostic biomarkers and elucidate on HCC immunotherapy.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients

et al. 2022

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“…Mutations that impact the intrinsic disorder protein regions (IDPRs) have been implicated in developing other neoplasms, including conjunctival melanoma and ocular surface squamous neoplasia [ 35 , 36 , 37 ]. Dysregulation of disordered regions that leads to dysfunction of BAP1 may have a role in the development of UM.…”

Section: Discussionmentioning

confidence: 99%

“…IDPRs are likely to be involved in an array of diverse biological functions [ 32 , 33 , 34 ]. Our group’s previous studies have demonstrated associations between IDPRs and the development of ocular surface squamous neoplasia and conjunctival melanoma [ 35 , 36 , 37 ]. Importantly, in a shift from structure-specific drug discovery campaigns, IDPRs have begun to be targeted to treat various cancers [ 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

Djulbegovic

Taylor

Uversky

et al. 2022

Genes

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Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein–protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1’s structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1’s intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm.

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“…The 127 TTN-coding sequence variants associated with human conditions are distributed as follows: 33 nonsense mutations, 32 frameshifts, 36 missense variants, and 22 splice-site variants [ 11 ]. Recent studies have indicated that mutations in the TTN gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN) [ 12 ]. TTN was identified as the most frequently mutated gene within the pancancer cohort, and its mutation number was best correlated with tumor mutation burden (TMB) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

TTN mutations predict a poor prognosis in patients with thyroid cancer

et al. 2022

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Objective: We aimed to investigate the relationship between titin (TTN) gene mutations and thyroid cancer (THCA) and to explore the feasibility of the TTN gene as a potential prognostic indicator of THCA. Methods: From TCGA-THCA cohort, we performed a series of analyses to evaluate the prognostic value and potential mechanism of TTN in THCA. These patients were divided into the mutant-type (MUT) group and the wild-type (WT) group. Differentially expressed genes (DEGs) in the two groups were screened using the ‘DESeq2’ R package. Functional enrichment analysis was performed, and the protein–protein interaction (PPI) network, transcription factor (TF)-target interaction networks, and competitive endogenous RNA (ceRNA) regulatory networks were established for the DEGs. The TIMER database was applied for immune cell infiltration. Survival analysis and Cox regression analysis were used to analyze the potential prognostic value of the TTN gene. Results: Differential expression analysis showed that 409 genes were significantly up-regulated and 36 genes were down-regulated. Functional enrichment analysis revealed that TTN gene mutations played a potential role in the development of THCA. Analysis of the immune microenvironment indicated that TTN gene mutations were significantly associated with enrichment of M0 macrophages. Survival analysis showed that the MUT group predicted poorer prognosis than the WT group. Cox regression analysis demonstrated that TTN gene mutations were an independent risk factor for THCA. Nomograms also confirmed the prognostic values of the TTN gene in THCA. Conclusions In summary, our results demonstrated that TTN gene mutations predict poor prognosis in patients with THCA. This is the first study to research TTN gene mutations in THCA and to investigate their prognostic value in THCA.

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Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia

Cited by 8 publications

References 27 publications

A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients

A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

TTN mutations predict a poor prognosis in patients with thyroid cancer

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Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia

Cited by 8 publications

References 27 publications

A CD8+ T cell‐related genes prognostic model for hepatocellular carcinoma patients

A CD8+ T cell‐related genes prognostic model for hepatocellular carcinoma patients

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma

TTN mutations predict a poor prognosis in patients with thyroid cancer

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Resources

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A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients

A CD8⁺ T cell‐related genes prognostic model for hepatocellular carcinoma patients