Analyzing PKC Gamma (+ 19,506 A/G) polymorphism as a promising genetic marker for HCV-induced hepatocellular carcinoma

Fizzah Abid; Talha Iqbal; Khushbukhat Khan; Yasmin Badshah; Janeen H Trembley; Naeem Mahmood Ashraf; Maria Shabbir; Tayyaba Afsar; Ali Almajwal; Suhail Razak

doi:10.1186/s40364-022-00437-6

Analyzing PKC Gamma (+ 19,506 A/G) polymorphism as a promising genetic marker for HCV-induced hepatocellular carcinoma

Biomark Res. 2022 Nov 30;10(1):87. doi: 10.1186/s40364-022-00437-6.

Authors

Fizzah Abid¹, Talha Iqbal¹, Khushbukhat Khan¹, Yasmin Badshah¹, Janeen H Trembley^{2

3

4}, Naeem Mahmood Ashraf⁵, Maria Shabbir⁶, Tayyaba Afsar⁷, Ali Almajwal⁷, Suhail Razak⁸

Affiliations

¹ Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
² Minneapolis VA Health Care System Research Service, Minneapolis, MN, USA.
³ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
⁵ School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan.
⁶ Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan. mshabbir@asab.nust.edu.pk.
⁷ Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, KSA, Saudi Arabia.
⁸ Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, KSA, Saudi Arabia. smarazi@ksu.edu.sa.

Abstract

Background: HCC is a major health concern worldwide. PKC gamma, a member of the conventional PKC subclass, is involved in many cancer types, but the protein has received little attention in the context of single nucleotide polymorphisms and HCC. Therefore, the study aims to investigate the association of PKC gamma missense SNP with HCV-induced hepatocellular carcinoma.

Methods: The PKC gamma nsSNPs were retrieved from the ENSEMBL genome browser and the deleterious nsSNPs were filtered out through involvingPredictSNP2, CADD, DANN, FATHMM, FunSeq2 and GWAVA. Among the filtered nsSNPs, nsSNP rs1331262028 was identified to be the most pathogenic one. Through involving I-TASSER, ProjectHOPE, I-Mutant, MUpro, mCSM, SDM, DynaMut and MutPred, the influence of SNP rs1331262028 on protein structure, function and stability was estimated. A molecular Dynamic simulation was run to determine the conformational changes in mutant protein structure compared to wild. The blood samples were collected for genotyping analysis and for assessing ALT levels in the blood.

Results: The study identified for the first time an SNP (rs1331262028) of PRKCG to strongly decrease protein stability and induce HCC. The RMSD, RMSF, and Rg values of mutant and wild types found were significantly different. Based on OR and RR values of 5.194 and 2.287, respectively, genotype analysis revealed a higher correlation between the SNP homozygous wild Typeform, AA, and the disease while patients with genotype AG have higher viral load.

Conclusion: Outcomes of the current study delineated PKC gamma SNP rs1331262028 as a genetic marker for HCV-induced HCC that could facilitate disease management after further validation.

Keywords: Alanine aminotransferase; Biomarker; K359R; Missense SNPs; PRKCG; Serine-threonine kinases.