Abstract
TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants identified in TP53, however, many remain functionally unclassified as variants of unknown significance (VUS) due to the lack of evidence. This is reflected by the presence of 749 (42%) VUS of the 1785 germline variants collected in the ClinVar database. In this study, we addressed the deleteriousness of TP53 missense VUS. Utilizing the protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method that we developed, we measured the effects of missense VUS on TP53 structural stability. Of the 340 missense VUS tested, we observed deleterious evidence for 193 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with those from other in silico methods and observed higher specificity of RPMDS in classification of TP53 missense VUS than these methods. Data from our current study address a long-standing challenge in classifying the missense VUS in TP53, one of the most important tumor suppressor genes.
Highlights
As one of the most important and studied tumor-suppressor genes, TP53 plays essential roles in maintaining genome stability through controlling cell cycle, activating DNA damage repair, and initiating apoptosis [1,2,3]
From the ClinVar database, we identified a total of 443 missense variants located within the TP53 DNA binding domain, including 80 known pathogenic, 23 known benign/likely benign, and 340 variants of unknown significance (VUS) (Supplementary Table S1)
The results indicate that Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) provides high sensitivity to detect deleterious missense VUS variants
Summary
As one of the most important and studied tumor-suppressor genes, TP53 plays essential roles in maintaining genome stability through controlling cell cycle, activating DNA damage repair, and initiating apoptosis [1,2,3]. While the majority of TP53 variation is somatic, germline variation frequently occurs and causes early development of multiple types of cancer, as represented by the Li-Fraumeni syndrome [5]. Unlike the frameshift or nonsense variants that commonly occur in many other tumor suppressors, germline variation in TP53 is mostly missense variant, causing single amino acid substitution, and is located mostly within the DNA binding domain (DBD) of TP53. Determination of the pathogenicity for the unclassified TP53 missense variants remains an obstacle in translating the rich knowledge of TP53 in tumorigenesis into clinical cancer applications. This is a common challenge in many cancer predisposition genes [7,8,9]
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