Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

Abstract

The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11

“…Some studies of NSCLC of mixed histologic subtypes do not show any prognostic impact of mutated TP53 [32,33]. Other reports, including ours, show worse survival in lung adenocarcinoma patients with mutations in TP53 [34,35]. However, separating the true prognostic and predictive impact of TP53, in relation to adjuvant therapy, has proven to be difficult [36].…”

TP53 mutations predict for poor survival in ALK rearrangement lung adenocarcinoma patients treated with crizotinib

“…Our study also found ALK positive patients with TP53 exon 8 mutation were poorer survival than other mutation types. The TP53 mutant type has been found to be an important factor for gefitinib-induced apoptosis in NSCLC cell lines and reduces gefitinib-induced apoptosis (26). We think that TP53 could have a role as prognostic factor to ALK inhibitors, rather than predictive factor.…”

Correlation Analysis Among the Level of IL‐35, Microvessel Density, Lymphatic Vessel Density, and Prognosis in Non‐Small Cell Lung Cancer

“…13,14 IL-35 may be widely involved in the immune response process in vivo and has become a research hotspot in cytokine research, as it provides a new perspective in the biological treatment of infectious diseases, autoimmune diseases, and tumors. 3,[15][16][17][18][19] Growing evidence now supports a role for IL-35 in tumor occurrence and development. For example, the level of plasma IL-35 was significantly higher in patients with NSCLC than in healthy controls (21.37 ± 11.55 pg/mL vs. 10.09 ± 5.32 pg/mL).…”