TP53 and CDKN2A mutations in patients with early-stage lung squamous cell carcinoma: an analysis of the correlations and prognostic outcomes

Abstract

Background: Lung squamous cell carcinoma (LUSC) is characterized by frequent mutations of tumor protein p53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A). However, to date, the impact of TP53/CDKN2A status on the clinical outcome of patients with early-stage LUSC is unclear.

Methods: Tissue samples from 16 early-stage, surgically resected LUSCs were analyzed by next-generation sequencing (NGS). Information regarding TP53 and CDKN2A alterations and patient survival time was downloaded from The Cancer Genome Atlas (TCGA) database. The associations between TP53 and CDKN2A status and tumor characteristics, outcomes including overall survival (OS) and disease-free survival (DFS), and mutation counts were investigated.

Results: TP53 and CDKN2A exhibited a high frequency of somatic mutations in early-stage LUSC in our center. Data for 1,176 samples were collected from TCGA. CDKN2A mutation status was associated with TP53 mutation status (P=0.040). TP53 mutation was a favorable prognostic factor for early-stage LUSC. The OS times of patients with wild-type and mutated TP53 were 28.94 and 60.48 months, respectively (P=0.002). In contrast, CDKN2A mutations were significantly associated with a shorter survival time in early-stage LUSC. The OS times for wild-type and mutated CDKN2A patients were 62.81 and 37.55 months, respectively (P=0.026). Patients with TP53 mutations had higher total mutation counts compared to patients with wild-type TP53. Furthermore, OS was significantly shorter in patients with a low mutation count compared to patients with a median or high mutation count.

Conclusions: Early-stage LUSC patients with TP53 mutations had a longer OS, while those with CDKN2A mutations had a shorter OS. Furthermore, patients with TP53 mutation/CDKN2A wild-type status had a longer OS. CDKN2A mutation is a vital indicator for prognostic assessment according to TP53 status. The prolonged survival of patients with TP53 mutations may be due to their high mutation counts. Larger datasets are required to validate these observations.

Keywords: Tumor protein p53 (TP53); cyclin dependent kinase inhibitor 2A (CDKN2A); lung squamous cell carcinoma (LUSC); mutation; prognosis.

Figure 1

Significantly mutated genes observed in early-stage, surgically resected lung squamous cell carcinoma (LUSC) samples obtained in our center. (A) The top 16 significantly mutated genes in LUSC samples. (B) A comparison of the mutation frequencies of significantly mutated genes between the southeastern China cohort and The Cancer Genome Atlas (TCGA) cohort of LUSC patients.

Figure 2

The distribution of tumor protein p53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) mutations in early-stage lung squamous cell carcinoma (LUSC). (A) The distribution of TP53 wild type (wt) or mutated type (mut). (B) The distribution of different TP53 mutation sites. (C) The distribution of different TP53 mutation types. (D) The distribution of TP53 mutation status divided into wild type, disruptive mutation, and nondisruptive mutation groups. (E) The distribution of CDKN2A wild type (wt) or mutated type (mut). (F) The distribution of different CDKN2A mutation sites.

Figure 3

Survival curves of patients carrying tumor protein p53 (TP53) mutations. (A) Overall survival (OS) in different tumor stages. (B) OS in TP53-mutated tumors of different stages. (C) OS in TP53 wild-type tumors of different stages. (D) OS in TP53 wild-type and TP53-mutated patients. (E) OS in stage III patients carrying wild-type or mutated TP53. (F) OS in patients carrying wild-type or mutated TP53 depending on the year of initial diagnosis. (G) OS in patients with wild-type and mutated TP53 subdivided according to mutation site. (H) OS in patients with wild-type and mutated TP53 subdivided according to mutation type. (I) OS in patients with wild-type and mutated TP53 subdivided into disruptive or nondisruptive mutation types.

Figure 4

Survival curves of patients carrying cyclin dependent kinase inhibitor 2A (CDKN2A) and tumor protein p53 (TP53) mutations. (A) Overall survival (OS) in patients with wild-type and mutated CDKN2A. (B) OS in patients with wild-type and mutated CDKN2A subdivided according to mutation site. (C) OS of patients in different CDKN2A/TP53 mutation groups. (D) OS according to different TP53 mutation sites in CDKN2A-mutated patients. (E) OS according to different TP53 mutation types in CDKN2A-mutated patients.

Figure 5

The correlation between mutation counts and tumor protein p53 (TP53) status and survival time. (A) Total mutation count in LUSC patients with wild-type and mutated TP53. (B) Total mutation count in lung squamous cell carcinoma (LUSC) patients with wild-type and mutated TP53 subdivided according to mutation site. (C) Total mutation count in LUSC patients with wild-type and mutated P53 subdivided according to mutation type. (D) Total mutation count in LUSC patients with wild-type and mutated P53 subdivided into disruptive or nondisruptive mutation types. (E) Total mutation count in LUSC patients with different cyclin dependent kinase inhibitor 2A (CDKN2A)/TP53 mutations. (F) Overall survival (OS) of early-stage LUSC patients subdivided into a low mutation count group (mutation count-L), a medium mutation count group (mutation count-M), and a high mutation count group (mutation count-H). For (A-E), each dot represents a patient [mean ± standard deviation (SD)]; *, P<0.05; **, P<0.01; ***, P<0.001.