Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients

Abstract

Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.

Prion‐like proteins: from computational approaches to proteome‐wide analysis

“…Of note, the interplay between compositional bias and the presence of short-amyloid stretches has enabled predicting mutations impact on the aggregation propensity of prion-like proteins [65,66] in various diseases related to mammalian prion-like protein variants [67][68][69][70].…”

Strong Association of the rs4986790 Single Nucleotide Polymorphism (SNP) of the Toll-Like Receptor 4 (TLR4) Gene with Human Immunodeficiency Virus (HIV) Infection: A Meta-Analysis

“…In addition, differences in the local crystal structure of the TLR4-MD2-LPS complex were noted between TLR4 with the wild type allele and the G299 allele [ 20 , 21 ]. Since genetic variations confer functional alteration, these studies indicate that the rs4986790 SNP of the TLR4 gene is related to anti-bacterial functions of TLR4 [ 22 , 23 , 24 ]. Interestingly, TLR4/MD2 complex directly interacts with the Tat protein of HIV-1, and HIV-1 modulates the expression level of TLR4 and downstream immune responses, including the NF-κB pathway [ 25 , 26 ].…”

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer

“…Interestingly, a specific analysis of PRNP gene mutations using the Cancer Genome Atlas (TCGA) database revealed a total of 48 somatic mutations in the PRNP gene in different cancers, encompassing lung adenocarcinoma, colorectal adenocarcinoma, endometrial carcinoma, head and neck squamous cell carcinoma, and melanoma [ 130 ]. Of note, five of these PRNP gene somatic mutations were considered to be pathogenic since they affect PrP C function, while four were identified as amyloid-prone PRNP somatic mutations [ 130 ]. Moreover, in pancreatic ductal adenocarcinoma cell line BxPC-3, Yang et al [ 131 ] identified six missense mutations in four major genes involved in the GPI anchor modification pathway which contributes to increased tumor cell motility.…”