Identification of a 6-Gene Signature Associated with Resistance to Tyrosine Kinase Inhibitors: Prognosis for Clear Cell Renal Cell Carcinoma

Li, Qinke; Yang, Wenbo; Lu, Maoqing; Zhang, Ronggui

doi:10.12659/msm.927078

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…The leading SNPs of PPP1R9A gene, located in locus 7q21.3, was the most significant SNP at rs78595611 (p = 9.73 × 10 –7 ) and SNP rs76361654 (p = 7.43 × 10 –6 ). PPP1R9A gene is involved in neurite formation, is associated to coronary artery disease, and is a prognostic marker in renal cancer 37 , 38 . Two leading SNPs of the cytochrome P450 enzymes ( CYP2B7P , rs4001941, p = 1.12 × 10 –6 ; CYP4F24P , rs117074522, p = 2.27 × 10 –6 ) that are involved in drug pharmacokinetics and response have also been associated with DKD in T2DM patients 39 .…”

Section: Resultsmentioning

confidence: 99%

A genome-wide association study identifies a possible role for cannabinoid signalling in the pathogenesis of diabetic kidney disease

Osman

Mousa

Albreiki

et al. 2023

Sci Rep

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Diabetic kidney disease (DKD), also known as diabetic nephropathy, is the leading cause of renal impairment and end-stage renal disease. Patients with diabetes are at risk for DKD because of poor control of their blood glucose, as well as nonmodifiable risk factors including age, ethnicity, and genetics. This genome-wide association study (GWAS) was conducted for the first time in the Emirati population to investigate possible genetic factors associated with the development and progression of DKD. We included data on 7,921,925 single nucleotide polymorphism (SNPs) in 258 cases of type 2 diabetes mellitus (T2DM) who developed DKD and 938 control subjects with T2DM who did not develop DKD. GWAS suggestive results (P < 1 × 10–5) were further replicated using summary statistics from three cohorts with T2DM-induced DKD (Bio Bank Japan data, UK Biobank, and FinnGen Project data) and T1DM-induced DKD (UK-ROI cohort data from Belfast, UK). When conducting a multiple linear regression model for gene-set analyses, the CNR2 gene demonstrated genome-wide significance at 1.46 × 10–6. SNPs in CNR2 gene, encodes cannabinoid receptor 2 or CB2, were replicated in Japanese samples with the leading SNP rs2501391 showing a Pcombined = 9.3 × 10–7, and odds ratio = 0.67 in association with DKD associated with T2DM, but not with T1DM, without any significant association with T2DM itself. The allele frequencies of our cohort and those of the replication cohorts were in most cases markedly different. In addition, we replicated the association between rs1564939 in the GLRA3 gene and DKD in T2DM (P = 0.016, odds ratio = 0.54 per allele C). Our findings suggest evidence that cannabinoid signalling may be involved in the development of DKD through CB2, which is expressed in different kidney regions and known to be involved in insulin resistance, inflammation, and the development of kidney fibrosis.

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Section: Resultsmentioning

confidence: 99%

A genome-wide association study identifies a possible role for cannabinoid signalling in the pathogenesis of diabetic kidney disease

Osman

Mousa

Albreiki

et al. 2023

Sci Rep

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“…Next, the penalized Lasso Cox proportional hazard regression model, which was an algorithm to prevent over-fitting of the model was employed to further determine the key prognostic genes. An effective prognostic model was constructed based on the expression levels and coefficients of these key genes, and the risk score formula was as follows: 24 …”

Section: Methodsmentioning

confidence: 99%

A Pyroptosis-Related Gene Signature Associated with Prognosis and Tumor Immune Microenvironment in Gliomas

Zhou¹,

Xu²,

Huang³

et al. 2022

IJGM

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Background Pyroptosis is a novel form of cell death that plays a significant role in cancer, while the prognostic values of pyroptosis-related genes in gliomas have not been revealed. Methods We analyzed the RNA-seq and clinical data of gliomas from the University of California Santa Cruz (UCSC) Xena database to determine differentially expressed pyroptosis-related genes. Based on these genes, a pyroptosis genes signature was constructed after univariate Cox analysis and Lasso Cox analyses. The sensitivity and specificity of pyroptosis genes signature were verified by the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, we explored the association of risk signatures with tumor microenvironment and immune cell infiltration. Results Of 15 differentially expressed pyroptosis-related genes, three genes of BCL2 associated X (BAX), caspase 3 (CASP3), and caspase 4 (CASP4) were used to construct the risk signature. The effectiveness of risk signature for predicting survival at 1, 3, 5 years was performed by the receiver operating characteristic curve (ROC), and the area under curves (AUC) was 0.739, 0.817, and 0.800, respectively. Functional enrichment results showed signal transduction, cell adhesion, immune response, and inflammatory response were enriched. The immune analysis revealed that pyroptosis had a remarkable effect on the immune microenvironment. Conclusion In this study, we constructed a pyroptosis-related gene signature, which can serve as a potential biomarker for predicting the survival of glioma patients. Additionally, we suggested that pyroptosis may promote gliomas development by inducing chronic inflammation microenvironment.

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“…Whilst the remaining upregulated mRNAs have not previously been shown to be upregulated specifically in SBTs, it is not surprising that these have been previously associated with the development of other cancers. For example, CFAP276 expression is associated with positive prognosis of renal clear cell carcinoma [582], GAS2L2 is mutated in cancer but functional significance is unknown [583], DNAH3 [584] and FAM81B [585] are upregulated in breast cancer and CERKL in cutaneous squamous cell carcinoma is associated with decreased ability to respond to oxidative stress [586].…”

Section: Specific Mirna Tissue Transcriptional Markers Of Serous Bord...mentioning

confidence: 99%

Identifying Novel Candidate Biomarkers of Early Epithelial Ovarian Cancer

Sczelecki¹

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Ovarian cancer (OC) is the fifth leading cause of cancer deaths in women, and is the most lethal gynaecological cancer worldwide, with the most common subtype being epithelial OC (EOC). The asymptomatic nature and limited understanding of early disease hampers research into early-stage OC and culminates in diagnostic methods only capable of detecting malignant markers of OC. Therefore, there is an urgent need for biomarkers of early-stage OC to be identified. The first aim of this thesis was to validate a unique mouse model of early OC development. The homozygous Fanconi anemia complementation group D2 knock-out mouse (Fancd2-/-) develops multiple ovarian tumor phenotypes in a sequential manner as they age. Our group previously identified by immunohistochemistry the purported initiating precursor cells, termed ‘sex cords’, that are hypothesised to progress into EOC in this model. To genetically validate this hypothesis, the sex cords, a late-stage tumor phenotype (tubulostromal adenoma), and Fancd2 wild-type (Fancd2+/+) granulosa cell and stromal controls, were isolated by laser-capture microdissection for downstream genetic investigation. Multiplexed gene expression analyses of ~ 90 selected genes were performed using the Genome Lab GeXP Genetic Analysis System (GeXP). Principal component analyses and unbiased hierarchical clustering of the resultant gene expression data determined that the gene signature profiles within sex cords and tubulostromal adenoma samples indeed clustered together genetically confirming the identity of a precursor lesion in this mouse model. Furthermore, key epithelial OC markers included in the GeXP assay (Pax8, Cdh1 and Muc16) were expressed in both the sex cords and tubulostromal adenoma demonstrating neoplastic transformation was already occurring in the precursor lesion. Despite confirmation of the identity and developmental origin of the precursor lesion (sex cords), an in-depth understanding of the model was limited due to restricted numbers of genes able to be investigated using the GeXP assay, thus unique markers of the precursor lesion were not identified. Therefore, the second aim of this thesis was to comprehensively investigate the genetic signature of the Fancd2-/- model via total and small RNA sequencing of micro-dissected cells of the sex cords, tubulostromal adenomas and the equivalent Fancd2+/+ controls. Sequencing results of matched messenger (m) RNAs and micro (mi) RNA expression in micro-dissected tissue of the phenotypes of interest provided novel information about the development of early EOC and unique transcriptional markers, namely upregulated Brinp2, Slc6a7, Smpd3, Grin2b, Grik4, AW55198, Lrp11 and Mro mRNAs and downregulated miR-122/b-5p, miR-129-5p, miR-138-5p, miR-465a/b/-3p, miR-465c-3p/5p, miR-500-3p and miR-129b-3p miRNAs of the sex cord phenotype through differential gene expression analysis. Whilst tissue markers of EOC are relevant as biomarkers of EOC, the location of the ovaries within the peritoneum prevents their diagnostic implementation without surgical intervention. To circumvent this limitation, liquid biopsy has become paramount for OC diagnosis. However, the detection of early biomarkers of EOC in humans is ultimately hampered by their low systemic concentration and the presence of circulating factors from all other organ systems. Therefore, to bypass detection limitations within systemic circulation, the next aim of this thesis was to leverage the established Fancd2-/- model of early EOC to provide proof of concept that secreted miRNA encapsulated into extracellular vesicles (EV) secreted from the precursor lesion (i.e., sex cords) could be detected in conditioned media from ovary explant culture. Performing RNA sequencing from EV-derived small RNAs isolated from conditioned culture medium resulted in the identification of five common upregulated secreted EV miRNAs in Fancd2-/- mouse ovaries that had sex cords or tubulostromal adenomas present, compared to their age-matched Fancd2+/+ counterparts. Additionally, the small RNA sequencing data of EVs was compared to the sequencing data of the micro-dissected sex cords and tubulostromal adenomas and these identical five miRNAs were also significantly upregulated as compared to the control group. This suggests that these five secreted EV miRNAs (miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-429-3p and miR-375-3p) originate from the sex cord and tubulostromal adenoma cells and therefore provided proof-of-concept that small transformational changes such as the development of a precursor lesion can be detected within secreted EVs. The final aim of this thesis was to determine whether the methodologies adopted for early candidate biomarker discovery in a murine model can be applied to human biopsy specimens and subsequently the relevance of the Fancd2-/- model for identifying novel biomarkers for human EOC. Two serous subtypes of human EOC, early low-grade serous borderline tumours (SBT; as an early phenotype) and high-grade serous ovarian cancer (HGSOC; as a late malignant phenotype) were selected for study. SBT and HGSOC specimens were prepared for matched micro-dissected neoplastic epithelial cells and explant cultures. Total and small RNA sequencing of micro-dissected tissue and small RNA sequencing of EVs from explant cultures were performed as per the mouse studies. This sequencing data resulted in the identification of SBT tissue-specific mRNA and miRNA markers as well as SBT-secreted miRNA markers. Remarkably, comparing the human and mouse sequencing data revealed an overlap in differentially expressed genes between the SBT, HGSOC, sex cords, and tubulostromal adenomas, pertaining to key epithelial markers of EOC (Muc16, Cdh1, Krt7, Krt19, Epcam) and the five secreted EV miRNAs firstly described in the murine studies. This provides strong evidence that these novel candidate biomarkers are relevant to early human EOC. Overall, the results from this thesis confirmed the relevance of the Fancd2 model for human OC investigation and identified novel candidate biomarkers of early EOC that may be applied to both the mouse model and human ovarian cancer.

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Identification of a 6-Gene Signature Associated with Resistance to Tyrosine Kinase Inhibitors: Prognosis for Clear Cell Renal Cell Carcinoma

Cited by 3 publications

References 45 publications

A genome-wide association study identifies a possible role for cannabinoid signalling in the pathogenesis of diabetic kidney disease

A genome-wide association study identifies a possible role for cannabinoid signalling in the pathogenesis of diabetic kidney disease

A Pyroptosis-Related Gene Signature Associated with Prognosis and Tumor Immune Microenvironment in Gliomas

Identifying Novel Candidate Biomarkers of Early Epithelial Ovarian Cancer

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