Single nucleotide polymorphisms as prognostic and predictive biomarkers in renal cell carcinoma

Garrigós, Carmen; Espinosa, Marta; Salinas, Ana; Osmán, Ignacio; Medina, Rafael; Tarón, Miguel; Molina-Pinelo, Sonia; Durán, Ignacio

doi:10.18632/oncotarget.22533

Cited by 16 publications

(9 citation statements)

References 41 publications

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“…4d) are located to chromosome 5 (cytoband q32), which is the location of the protein-coding gene. The highest association is found for variant rs3816018, which has been previously reported in Garrigos et al [39] and Benson et al [40]. Interestingly, the chromosomal analysis shows that heterozygote individuals for the protein variant have intermediate levels of blood protein levels (Fig.…”

Section: Genome-wide Association Analysis Of the Blood Protein Profilessupporting

confidence: 58%

Whole-genome sequence association analysis of blood proteins in a longitudinal wellness cohort

et al. 2020

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Background: The human plasma proteome is important for many biological processes and targets for diagnostics and therapy. It is therefore of great interest to understand the interplay of genetic and environmental factors to determine the specific protein levels in individuals and to gain a deeper insight of the importance of genetic architecture related to the individual variability of plasma levels of proteins during adult life. Methods: We have combined whole-genome sequencing, multiplex plasma protein profiling, and extensive clinical phenotyping in a longitudinal 2-year wellness study of 101 healthy individuals with repeated sampling. Analyses of genetic and non-genetic associations related to the variability of blood levels of proteins in these individuals were performed. Results: The analyses showed that each individual has a unique protein profile, and we report on the intraindividual as well as inter-individual variation for 794 plasma proteins. A genome-wide association study (GWAS) using 7.3 million genetic variants identified by whole-genome sequencing revealed 144 independent variants across 107 proteins that showed strong association (P < 6 × 10 −11) between genetics and the inter-individual variability on protein levels. Many proteins not reported before were identified (67 out of 107) with individual plasma level affected by genetics. Our longitudinal analysis further demonstrates that these levels are stable during the 2-year study period. The variability of protein profiles as a consequence of environmental factors was also analyzed with focus on the effects of weight loss and infections. Conclusions: We show that the adult blood levels of many proteins are determined at birth by genetics, which is important for efforts aimed to understand the relationship between plasma proteome profiles and human biology and disease.

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Section: Genome-wide Association Analysis Of the Blood Protein Profilessupporting

confidence: 58%

Whole-genome sequence association analysis of blood proteins in a longitudinal wellness cohort

et al. 2020

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“…SNPs (Single Nucleotide Polymorphism) were also estimated to be responsible for more than 90 per cent of sequence variations in the human genome [ 15 ]. However, non-synonymous SNP (nsSNPs) are prioritized mainly because of their involvement in most of the human genetic diseases and their role in disease diagnosis as a biomarker [ 16 ]. Furthermore, these nsSNPs may induce amino acid substitutions in the protein sequence which can cause destabilizing conditions of the protein, including loss of stability or interaction between proteins [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Computational and structural based approach to identify malignant nonsynonymous single nucleotide polymorphisms associated with CDK4 gene

et al. 2021

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Cycline-dependent kinase 4 (CDK4), an enzyme of the cycline dependent or Ser/Thr protein kinase family, plays a role in cell cycle progression (G1 phase) by phosphorylating a tumor suppressor protein called pRB. Alteration of this enzyme due to missense mutation/ nonsynonymous single nucleotide polymorphisms (nsSNPs) are responsible for various types of cancer progression, e.g. melanoma, lung cancer, and breast cancer. Hence, this study is designed to identify the malignant missense mutation of CDK4 from the single nucleotide polymorphism database (dbSNP) by incorporating computational algorithms. Out of 239 nsSNPs; G15S, D140Y and D140H were predicted to be highly malignant variants which may have a devastating impact on protein structure or function. We also found defective binding motif of these three mutants with the CDK4 inhibitor ribociclib and ATP. However, by incorporating molecular dynamic simulation, our study concludes that the superiority of G15S than the other two mutants (D140Y and D140H) in destabilizing proteins nature.

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“…In the same study, this polymorphism was associated to better survival [37]. However, it was reported as significantly associated with worse prognosis in renal cell carcinoma [38]. Effect of synonymous variation on protein expression could be the result of organ specificity.…”

Section: Pdgfrα Staining Pattern and Mutational Status In Crcmentioning

confidence: 84%

Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size

et al. 2020

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Background Platelet derived growth factor receptor alpha (PDGFRα) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFRα protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction. Methods Our study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFRα expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls. Results PDGFRα staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFRα overexpression. This overexpression was significantly associated with mutations in exon 18 (P = 0.024), RAS wild type status (P < 10–3), tumor diameter (P = 0.048), whereas there was no association with tumor side (P = 0.13) and other clinicopathological features. Conclusion Overexpression of PDGFRα in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFRα overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.

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Single nucleotide polymorphisms as prognostic and predictive biomarkers in renal cell carcinoma

Cited by 16 publications

References 41 publications

Whole-genome sequence association analysis of blood proteins in a longitudinal wellness cohort

Whole-genome sequence association analysis of blood proteins in a longitudinal wellness cohort

Computational and structural based approach to identify malignant nonsynonymous single nucleotide polymorphisms associated with CDK4 gene

Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size

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