Dataset Information

Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability.

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.

SUBMITTER: Tam B

PROVIDER: S-EPMC8583684 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability.

Tam Benjamin B Sinha Siddharth S Qin Zixin Z Wang San Ming SM

International journal of molecular sciences 20211020 21

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 d ...[more]

PMID: 34768775

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Project description:Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinase-substrate relationship, and evolutionary conservation algorithms SIFT, PolyPhen and Align-GVGD. We evaluated whether 191 BRCA1 and 43 BRCA2 VUS from the Breast Cancer Information Core (BIC) database can functionally alter the consensus phosphorylation motifs and abolish kinase recognition and binding to sites known to be phosphorylated in vivo. Our results show that 13.09% (25/191) BRCA1 and 13.95% (6/43) BRCA2 VUS altered the phosphorylation of BRCA1 and BRCA2. We highlight six BRCA1 (K309T, S632N, S1143F, Q1144H, Q1281P, S1542C) and three BRCA2 (S196I, T207A, P3292L) VUS as potentially clinically significant. These occurred rarely (n<2 in BIC), mutated evolutionarily conserved residues and abolished kinase binding to motifs established in the literature involved in DNA repair, cell cycle regulation, transcription or response to DNA damage. Additionally in vivo phosphorylation sites identified via through-put methods are also affected by VUS and are attractive targets for studying their biological and functional significance. We propose that rare VUS affecting phosphorylation may be a novel and important mechanism for which BRCA1 and BRCA2 functions are disrupted in breast cancer.

Project description:Traditional cancer treatment approaches are often hindered by the presence of toxic side effects and the high rate of relapse observed in treated organs. In contrast, novel immunotherapeutic strategies targeting immune checkpoint inhibitors, particularly PD-1, have demonstrated promising results with minimal adverse effects. However, the emergence of immunotherapeutic-resistant tumors, predominantly caused by intrinsic mutations, poses a significant obstacle to successful treatment outcomes. Consequently, the primary objective of this study was to screen for the most detrimental missense mutations in the PD-1 gene associated with immunotherapeutic resistance. To achieve this aim, a comprehensive screening process utilizing 20 web servers, incorporating both sequence- and structure-based methodologies, was undertaken. Through meticulous analysis and mutual disease association sorting, four specific missense mutations were successfully identified. These mutations, namely, R38C, D61V, R94C, and D117V, emerged as the leading contributors to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The findings presented in this study are supported by multiple lines of evidence. A thorough examination of protein topology, structural alignment, docking interactions with PD-L1, and protein flexibility collectively confirmed the pathogenic nature of these sorted mutations. By considering these various aspects, we have gained a comprehensive understanding of the underlying mechanisms driving immunotherapeutic resistance. In conclusion, the comprehensive screening process undertaken in this study has successfully identified R38C, D61V, R94C, and D117V as the primary mutations contributing to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The integration of protein topology analysis, structural alignment, docking studies with PD-L1, and assessment of protein flexibility have collectively provided robust evidence to support the pathogenic significance of these mutations.

Dataset Information

Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability.

Publications

Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability.

Similar Datasets

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