Identification of NRAS diagnostic biomarkers and drug targets for endometrial cancer—an integrated in silico approach

Larsen Alessandro, Kat Jun Eric Low, Aisha Abushelaibi, Swee Hua Erin Lim, Wan Hee Cheng, Sook Keng Chang, Kok Song Lai, Yap Wai Sum, Sathiya Maran

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Abstract

The diagnosis of endometrial cancer involves sequential, invasive tests to assess the thickness of the endometrium by a transvaginal ultrasound scan. In 6–33% of cases, endometrial biopsy results in inadequate tissue for a conclusive pathological diagnosis and 6% of postmenopausal women with non-diagnostic specimens are later discovered to have severe endometrial lesions. Thus, identifying diagnostic biomarkers could offer a non-invasive diagnosis for community or home-based triage of symptomatic or asymptomatic women. Herein, this study identified high-risk pathogenic nsSNPs in the NRAS gene. The nsSNPs of NRAS were retrieved from the NCBI database. PROVEAN, SIFT, PolyPhen-2, SNPs&GO, PhD-SNP and PANTHER were used to predict the pathogenicity of the nsSNPs. Eleven nsSNPs were identified as “damaging”, and further stability analysis using I-Mutant 2.0 and MutPred 2 indicated eight nsSNPs to cause decreased stability (DDG scores < −0.5). Post-translational modification and protein–protein interactions (PPI) analysis showed putative phosphorylation sites. The PPI network indicated a GFR-MAPK signalling pathway with higher node degrees that were further evaluated for drug targets. The P34L, G12C and Y64D showed significantly lower binding affinity towards GTP than wild-type. Furthermore, the Kaplan–Meier bioinformatics analyses indicated that the NRAS gene deregulation affected the overall survival rate of patients with endometrial cancer, leading to prognostic significance. Findings from this could be considered novel diagnostic and therapeutic markers.

Original languageEnglish
Article number14285
Number of pages14
JournalInternational Journal of Molecular Sciences
Volume23
Issue number22
DOIs
Publication statusPublished - Nov 2022

Keywords

  • diagnostic markers
  • endometrial carcinoma
  • NRAS gene
  • prognostic gene
  • protein–ligand interactions

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