TP53 Mutation Spectrum in Smokers and Never Smoking Lung Cancer Patients

Abstract

Background: TP53 mutations are among the most common mutations found in lung cancers, identified as an independent prognostic factor in many types of cancers. The purpose of this study was to investigate the frequency and prognostic impact of TP53 mutations in never-smokers and in different histological subtypes of lung cancer.Methods: We analyzed tumor tissue from 394 non-small cell carcinomas including adenocarcinomas (n = 229), squamous cell carcinomas (n = 112), large cell carcinomas (n = 30), and others (n = 23) for mutations in TP53 by the use of Sanger sequencing (n = 394) and next generation sequencing (n = 100).Results: TP53 mutations were identified in 47.2% of the samples, with the highest frequency (65%) of mutations among squamous cell carcinomas. Among never-smokers, 36% carried a TP53 mutation, identified as a significant independent negative prognostic factor in this subgroup. For large cell carcinomas, a significantly prolonged progression free survival was found for those carrying a TP53 mutation. In addition, the frequency of frameshift mutations was doubled in squamous cell carcinomas (20.3%) compared to adenocarcinomas (9.1%).Conclusion: TP53 mutation patterns differ between the histological subgroups of lung cancers, and are also influenced by smoking history. This indicates that the histological subtypes in lung cancer are genetically different, and that smoking-induced TP53 mutations may have a different biological impact than TP53 mutations occurring in never-smokers.

Somatic genome alterations in relation to age in lung adenocarcinoma

“…Although previous studies revealed that the number of TP53 mutations are common in noncancerous tissue and accumulate with age and tobacco consumption, we detected an overall higher rate of TP53 mutations in younger patients particularly in <50 and 50–60 age groups. TP53 mutations showed a strong enrichment of smoking related SI4 and aflatoxin related SI24, both constituted of C>A transversions, indicating guanine damages that are being repaired by transcription‐coupled nucleotide excision repair.…”

“…Considering the crucial roles of p53 in maintaining genome stability, the loss or disruption of p53 function can lead to uncontrolled cell proliferation and cancer . Past studies demonstrated that the frequency of TP53 mutations increased with tobacco consumption . Therefore, the relation between TP53 mutations, tobacco consumption and patient age remains an open question.…”

“…7 Past studies demonstrated that the frequency of TP53 mutations increased with tobacco consumption. [15][16][17] Therefore, the relation between TP53 mutations, tobacco consumption and patient age remains an open question.…”

Large scale analysis of smoking-induced changes in the tumor immune microenvironment

“…Tobacco smoke contains many carcinogenic components that damage DNA and increase the overall rate of mutation, affect methylation patterns and modify gene expression profiles, all of which affect the risk of cancer initiation and progression. An example of a gene affected by smoking is P53 with almost twice the mutation rate in smokers vs. never-smokers 2 . Chemical features of nicotine and other compounds in tobacco smoke result in a specific DNA mutation signature in cancer patients smoking tobacco 3 and analysis of the effects of smoking on cancer historically focused on defining and understanding the molecular mechanisms of such signatures.…”

Standardizing Biomarker Testing for Canadian Patients with Advanced Lung Cancer

“…TP53 mutations are common, present in approximately 50% of lung cancers, and are prognostic of poor outcomes 6,85 . Mutations in this gene deactivate the G1 cell-cycle checkpoint 6 .…”