Pathogenic nsSNPs that increase the risks of cancers among the Orang Asli and Malays

Abstract

Single-nucleotide polymorphisms (SNPs) are the most common genetic variations for various complex human diseases, including cancers. Genome-wide association studies (GWAS) have identified numerous SNPs that increase cancer risks, such as breast cancer, colorectal cancer, and leukemia. These SNPs were cataloged for scientific use. However, GWAS are often conducted on certain populations in which the Orang Asli and Malays were not included. Therefore, we have developed a bioinformatic pipeline to mine the whole-genome sequence databases of the Orang Asli and Malays to determine the presence of pathogenic SNPs that might increase the risks of cancers among them. Five different in silico tools, SIFT, PROVEAN, Poly-Phen-2, Condel, and PANTHER, were used to predict and assess the functional impacts of the SNPs. Out of the 80 cancer-related nsSNPs from the GWAS dataset, 52 nsSNPs were found among the Orang Asli and Malays. They were further analyzed using the bioinformatic pipeline to identify the pathogenic variants. Three nsSNPs; rs1126809 (TYR), rs10936600 (LRRC34), and rs757978 (FARP2), were found as the most damaging cancer pathogenic variants. These mutations alter the protein interface and change the allosteric sites of the respective proteins. As TYR, LRRC34, and FARP2 genes play important roles in numerous cellular processes such as cell proliferation, differentiation, growth, and cell survival; therefore, any impairment on the protein function could be involved in the development of cancer. rs1126809, rs10936600, and rs757978 are the important pathogenic variants that increase the risks of cancers among the Orang Asli and Malays. The roles and impacts of these variants in cancers will require further investigations using in vitro cancer models.

Genome-wide association study of actinic keratosis identifies new susceptibility loci implicated in pigmentation and immune regulation pathways

“…The association of rs1393350 and AK risk reached a genome-wide level of significance in our study, and we identified an additional lead SNP rs1126809 at the TYR locus. SNP rs1126809 has been associated with a low tan response and increased risk of keratinocyte carcinomas and melanoma 16 , 18 , 24 , 25 , 31 , and it may cause changes at the post-translational modification site, leading to dysregulation of melanin synthesis within the melanosomes 32 . Similarly, SNP rs16891982 lies in SLC45A2 , which encodes a transporter protein that mediates melanin synthesis, correlates with reduced melanin content in cultured human melanocytes 33 .…”

Investigation of pathogenic germline variants in gastric cancer and development of “GasCanBase” database

“…4,12,13 They can alter protein functions by inactivating active sites of enzymes, deflecting the folding patterns, changing the solubility and stability, and so on. [14][15][16][17] Moreover, nsSNPs have a significant impact on the functional diversity of coded proteins and are found to promote pathogenesis in various types of cancer, 18,19 sickle-cell anemia, 20 β-thalassemia, 21 cystic fibrosis, 22 Alzheimer's disease, and so forth. 23 Gastric cancer (GC), commonly known as stomach cancer, continues to be one of the deadliest types of cancer in the world, with the third-highest lethality and the fourth-highest morbidity rate.…”

“… 4 , 12 , 13 They can alter protein functions by inactivating active sites of enzymes, deflecting the folding patterns, changing the solubility and stability, and so on. 14 , 15 , 16 , 17 Moreover, nsSNPs have a significant impact on the functional diversity of coded proteins and are found to promote pathogenesis in various types of cancer, 18 , 19 sickle‐cell anemia, 20 β‐thalassemia, 21 cystic fibrosis, 22 Alzheimer's disease, and so forth. 23 …”

An Integrated Computational Analysis of High-Risk SNPs in Angiopoietin-like Proteins (ANGPTL3 and ANGPTL8) Reveals Perturbed Protein Dynamics Associated with Cancer

“…The non-synonymous single-nucleotide polymorphisms (nsSNPs) in proteins perturb their structure and function. nsSNPs are single-base changes leading to a change in the amino acid sequence of the encoded protein, and several of these variants are associated with disease [ 13 , 14 ]. These nsSNPs can affect important biological pathways by disrupting protein–protein interaction [ 15 ], inducing changes in protein conformation [ 16 ], or affecting the post-translational modification sites [ 17 ].…”

“…nsSNP mutations in oncoproteins are frequently observed in cancer, and an attempt to restore their functionality is a recent therapeutic strategy. Recent studies revealed that the utilization of in silico approaches for evaluating protein–protein interactions and analyzing SNPs provided evidence that mutations are associated with various disease conditions [ 13 , 14 , 21 ].…”