The influence ofTP53mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations

Abstract

A large number of studies have evaluated the impact of TP53 mutations on the prognosis of patients with non-small cell lung cancer (NSCLC); however, the results of these studies are still controversial. Recently, considerable intratumor heterogeneity for genetic alterations has been demonstrated in various human cancers, including lung cancer. In the present study, we evaluated TP53 mutations in NSCLCs by direct sequencing and observed remarkable variation in the values of relative intensity (RI, the height of the peak of mutated allele/the height of the peak of non-mutated allele) of the mutations. We also examined whether the RI values were associated with intratumor heterogeneity of TP53 mutations. In addition, we evaluated the relationship between TP53 mutations and survival outcome. The patients with a TP53 mutation did not have significantly worse survival compared to those without the mutation. However, when tumors with a TP53 mutation were categorized into two groups, those with a low and those with a high RI, the latter group had significantly worse survival compared to those with wild-type TP53 (adjusted hazard ratio = 2.58, 95% confidence interval = 1.21-5.48, P = 0.01), whereas the former group did not. These results suggest that intratumor genetic heterogeneity may be an important factor in determining the role of TP53 mutations on the prognosis of NSCLC patients.

TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis

“…Poeta et al (45) reported that a disruptive TP53 alteration, as compared with the wild-type, had an independent, significant association with decreased survival. In the study of Lee et al (19), neither disruptive nor non-disruptive mutations were significantly associated with the survival rate of the patients. However, these various TP53 genotypes were not mentioned in other studies that were included in this meta-analysis.…”

“…Several studies indicated that patients with mutations of TP53 survived for a shorter period of time (15–18), whereas others reported that there was no significant correlation between TP53 mutation and the survival rate (19–22). The present study aimed to present a meta-analysis of the available data on the prognostic significance of TP53 gene mutations in patients with NSCLC.…”

Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

“…Interestingly, even among the studies that did identify sub-clonality, there is disagreement regarding its clinical significance with some associating sub-clonality with shorter time to progression [ 9 , 22 ], whereas others report lack of clinical associations [ 11 , 14 , 25 ]. Moreover, low frequency TP53 mutant allele fraction, interpreted as sub-clonality, was associated with better survival in cases of lung carcinoma [ 37 ].…”

“…Evaluation of the tumor cell content in the sample is essential to differentiate between true sub-clonality and low tumor cell content. A study linking high frequency TP53 mutations with worse prognosis [ 37 ] is also limited by the lack of correction for tumor cell fraction. A molecular morphometric approach, like the one used in the present study should be able to accurately determine sub-clonality in intermixed tumor and also account for the tumor cell content in the sample.…”

Using the New CellCollector to Capture Circulating Tumor Cells from Blood in Different Groups of Pulmonary Disease: A Cohort Study

“…Here, we found that all of the CTC positive patients had SMARCB1 gene mutations in the CTC genome, suggesting that SMARCB1 may have a relationship in the early stage of lung cancer. TP53 was found not only as a prognosis marker in early stage lung cancer but also as an important event in cancer development 63 . Here, TP53 mutations, which frequently exist in early tumor cells, were found in the identified CTCs, showing that those CTCs may come from early stage tumor tissue.…”