TY - JOUR
T1 - Identification of NRAS diagnostic biomarkers and drug targets for endometrial cancer—an integrated in silico approach
AU - Alessandro, Larsen
AU - Low, Kat Jun Eric
AU - Abushelaibi, Aisha
AU - Lim, Swee Hua Erin
AU - Cheng, Wan Hee
AU - Chang, Sook Keng
AU - Lai, Kok Song
AU - Sum, Yap Wai
AU - Maran, Sathiya
N1 - Funding Information:
This research was funded by Interdisciplinary Research Grant from the Higher Colleges of Technology (Interdisciplinary_213346). The APC was funded by INTI International University.
Publisher Copyright:
© 2022 by the authors.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - diagnostic markers
KW - endometrial carcinoma
KW - NRAS gene
KW - prognostic gene
KW - protein–ligand interactions
UR - http://www.scopus.com/inward/record.url?scp=85142815894&partnerID=8YFLogxK
U2 - 10.3390/ijms232214285
DO - 10.3390/ijms232214285
M3 - Article
C2 - 36430761
AN - SCOPUS:85142815894
SN - 1661-6596
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 22
M1 - 14285
ER -