Genomic analysis of early-stage lung cancer reveals a role for TP53 mutations in distant metastasis

Abstract

Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I-III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases.

Figure 1

TP53 mutations are significantly associated with the development of distant metastases after diagnosis in early-stage NSCLC. (A) Overview of study design. (B) Cox regression hazard ratios of each mutation and copy number alteration analyzed, with significant results (α = 0.05) in red. Error bars are Bonferroni-adjusted 95% confidence intervals. (C) Kaplan–Meier curves showing time to first distant metastasis among patients with early-stage disease, stratified by TP53 mutation status in the primary tumor. Error bars are 95% confidence intervals. (D) Cox regression hazard ratios for TP53 mutation for metastasis to individual sites, with significant results (α = 0.05) in red. Error bars are Bonferroni-adjusted 95% confidence intervals. (E) Fraction of patients diagnosed at each stage, stratified by TP53 mutation status. Error bars denote 95% confidence intervals. (F) Kaplan–Meier curves showing overall survival probability stratified by TP53 mutation status, for patients diagnosed with stage I-III disease. Error bars are 95% confidence intervals. Colors for all panels denote primary tumor TP53 mutation status (dark blue: mutant, teal: wild-type). In all Cox regressions, we incorporated age, sex, race, ethnicity, smoking history, stage at diagnosis, and 10 total mutations/copy number alterations as covariates (Methods).

Figure 2

TP53 SNVs are found in the DNA binding domain and are associated with smoking. (A) Location of nonsynonymous SNVs and/or frameshift indels in the TP53 gene in primary tumor samples from stage I-IV NSCLC patients. The location of the p53 DNA binding domain is shown as an orange shaded region. (B) Fraction of patients with a TP53 mutation, stratified by smoking history. (C) Frequency of specific nonsynonymous single nucleotide substitutions in TP53 in patients without a history of smoking (light grey) and patients with a history of smoking (dark grey). In (B) and (C), error bars denote 95% Bayesian credible intervals. (D) Location of nonsynonymous SNVs and frameshift indels in smokers and nonsmokers, with amino acid position 158 highlighted in red.