Higher TP53 somatic mutation prevalence from liquid biopsy analysis in ever smoker non-small-cell lung cancer patients

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2023-11-28 DOI:10.1016/j.mrfmmm.2023.111847

Haktan Bağış Erdem , Mustafa Tarık Alay , Zeynep Özdemir , Ezgi Çevik , Öztürk Ateş , Cengiz Karaçin , İbrahim Şahin , Mutlu Doğan , Taha Bahsi

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Abstract

Objective

Cigarette smoking is a primary risk factor, linked to 80% of LC deaths. TP53, a key gene, is implicated in various cancers, with TP53 alterations in 36.7% of cancers. This research aims to investigate TP53 mutations detected in NSCLC patients by liquid biopsy and explore the relationship between these mutations and smoking history.

Material and method

The study enrolled a total of 340 patients diagnosed with non-small cell lung cancer (NSCLC). For sequencing, the Illumina NextSeq 500 system was utilized. The oncogenicity of the variants was assessed according to the ClinGen/CGC/VICC SOP and the variants were categorized into four tiers according to AMP/ASCO/CAP.

Results

The most common mutations were in TP53 (48.7%), followed by EGFR, PIK3CA, and PTEN. Missense mutations were frequent, with TP53 and EGFR having higher rates in ever-smokers. No indels or complex mutations were found in ever-smokers. Patient age ranged from 20 to 86 years. Tier I-II variants were more common in ever-smokers, while Tier III variants were prevalent in never-smokers. TP53 mutations were more frequent in ever-smokers, showing a strong association with smoking. Domain distribution showed differences in PIK3CA. Transversion/transition ratios varied by gene and smoking status.

Discussion

The presence of TP53 mutations is strongly associated with both cigarette smoking and elevated Tv/Ti ratios. The tier status of TP53, EGFR, and PTEN variants does not show a specific domain distribution, but interesting associations are observed between the tier status and domain distribution in PIK3CA variants. Therefore, further comprehensive investigations are needed to explore this entity, as well as the underlying factors contributing to the increased Tv/Ti rates in the TP53 gene. Such research will provide deeper insights into the genetic alterations associated with smoking and tumor heterogeneity, ultimately aiding in the development of targeted therapies.

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从不吸烟的非小细胞肺癌患者的液体活检分析中发现更高的TP53体细胞突变患病率

目的吸烟是主要的危险因素，与80%的肺癌死亡有关。TP53是一种关键基因，与多种癌症有关，36.7%的癌症发生了TP53改变。本研究旨在探讨液体活检在NSCLC患者中检测到的TP53突变，并探讨这些突变与吸烟史的关系。材料和方法本研究共纳入340例诊断为非小细胞肺癌(NSCLC)的患者。测序使用Illumina NextSeq 500系统。根据ClinGen/CGC/VICC SOP评估变异的致癌性，并根据AMP/ASCO/CAP将变异分为4级。结果TP53突变最多(48.7%)，其次为EGFR、PIK3CA和PTEN。错义突变很常见，TP53和EGFR在吸烟者中发病率更高。在长期吸烟者中没有发现基因突变或复杂突变。患者年龄20 ~ 86岁。I-II级变异在吸烟者中更为常见，而III级变异在从不吸烟者中普遍存在。TP53突变在长期吸烟者中更为常见，显示出与吸烟的强烈关联。PIK3CA结构域分布存在差异。变性/过渡比率因基因和吸烟状况而异。TP53突变的存在与吸烟和Tv/Ti比值升高密切相关。TP53、EGFR和PTEN变异体的层状态没有显示出特定的结构域分布，但在PIK3CA变异体的层状态和结构域分布之间观察到有趣的关联。因此，需要进一步的综合研究来探索这一实体，以及导致TP53基因中Tv/Ti比率增加的潜在因素。这样的研究将为吸烟和肿瘤异质性相关的基因改变提供更深入的见解，最终有助于开发靶向治疗。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.