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.
Highlights
Lung cancer is one of the most common types of cancers, and due to its aggressiveness, this disease is positioned as the most deadly cancer disease worldwide (Ferlay et al, 2015)
Lung cancers can be divided into small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC), consisting of adenocarcinomas (AC), squamous cell carcinomas (SCC), and large cell carcinomas (LCC) (Travis, 2014)
In order to explore the distribution of TP53 mutations in lung cancer and their impact on survival in the different histological subgroups, we have investigated TP53 mutations in 394 non-small cell lung carcinomas, and correlated this with smoking history and clinical data, such as survival, stage, tumor size, EGFR mutation status and histology
Summary
Lung cancer is one of the most common types of cancers, and due to its aggressiveness, this disease is positioned as the most deadly cancer disease worldwide (Ferlay et al, 2015). The TP53 protein is involved in regulation of essential cell activities, like the cell cycle, cell death, cell differentiation, DNA repair, and formation of blood vessels (Lane and Levine, 2010), and has been called “the guardian of the genome.” These pathways are involved in processes required to become a cancerous cell, and comprises several of the hallmarks of cancer, such as sustained angiogenesis and evading apoptosis (Hanahan and Weinberg, 2011). Research has shown that mutations in the TP53 gene are frequent in almost all types of cancers (Hollstein et al, 1991), and are present in approximately 50% of all NSCLC (Toyooka et al, 2003). 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
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