Clinical significance and prospective mechanism of increased CDKN2A expression in small cell lung cancer

Abstract

Background: Although it has been shown that cyclin dependent kinase inhibitor 2A (CDKN2A) plays a significant role in a number of malignancies, its clinicopathological value and function in small cell lung cancer (SCLC) is unclear and warrants additional research.

Methods: The clinical significance of CDKN2A expression in SCLC was examined by multiple methods, including comprehensive integration of mRNA level by high throughput data, Kaplan-Meier survival analysis for prognostic value, and validation of its protein expression using in-house immunohistochemistry.

Results: The expression of CDKN2A mRNA in 357 cases of SCLC was evidently higher than that in the control group (n = 525) combing the data from 20 research centers worldwide. The standardized mean difference (SMD) was 3.07, and the area under the curve (AUC) of summary receiver operating characteristic curve (sROC) was 0.97 for the overexpression of CDKN2A. ACC, COAD, KICH, KIRC, PCPG, PRAD, UCEC, UVM patients with higher CDKN2A expression had considerably worse overall survival rates than those with lower CDKN2A expression with the hazard ratio (HR) > 1.

Conclusion: CDKN2A upregulation extensively enhances the carcinogenesis and progression of SCLC.

Keywords: Clinical significance; Cyclin dependent kinase inhibitor 2A; Immunohistochemistry; Kaplan–Meier survival analysis; Small cell lung cancer.

Fig. 1

Violin plots of CDKN2A mRNA expression in SCLC. Wilcoxon rank test results are used to obtain the p-value. ^NSp ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 2

CDKN2A expression and its clinical significance in SCLC. Panel A: Forest maps of CDKN2A mRNA expression in SCLC and control tissues. Panel B: Publication bias evaluation of SMD (Begg’s p = 0.170). Panel C: CDKN2A’s ability to identify SCLC samples from non-SCLC samples. Panels D, E: Association of CDKN2A with prognosis in SCLC patients. Panel F: CDKN2A protein levels in SCLC and control groups. TMA tissue microarray. P-value was determined using the Wilcoxon rank sum test, ***p < 0.001

Fig. 3

CDKN2A expression in SCLC tissue and control samples under the microscope, the positive sites were located in the nucleus and cytoplasm. Figures A and B were protein expression level of CDKN2A in control group, figures C and D were protein level expression of CDKN2A in SCLC. The left figure was 200×, and the right figure was 400×

Fig. 4

The protein expression of FOXA1 was checked with immunohistochemistry. FOXA1 protein located at nucleus and cytoplasm, was measured in non-cancerous lung tissues (Figure A and B) and small cell lung cancer (SCLC) (Figure C and D). The magnification factor of Figure A and C was 200 × ; Figure B and D was 400 ×

Fig. 5

FOXA1 mRNA expression in SCLC and potential molecular mechanism of CDKN2A in SCLC. (A) Expression of FOXA1 in SCLC. (B) Potential molecular mechanism of CDKN2A in SCLC

Fig. 6

Expression of CDKN2A in a variety of tumors and the ability of CDKN2A to distinguish tumor tissue and control tissue. (A) Expression of CDKN2A in various tumor types and the corresponding control populations. (B) The ability of CDKN2A to differentiate the tumor tissue from control tissue

Fig. 7

Relationship between CDKN2A expression and cancer patient’s overall and disease-specific survival. (A, B): Patients with high CDKN2A expression were at a higher risk of developing cancer (A) and had a worse chance of surviving their disease (B). (C, D) Patients whose tumors express CDKN2A were at increased risk (C), and this correlation was shown to be predictive of a shorter disease-specific survival time (D)

Fig. 8

Association between CDKN2A expression and cancer-specific survival and progression-free survival. (A, B) Shorter disease-free survival time was associated with higher CDKN2A expression (A), which was a risk factor for some cancer patients (B). (C, D) Patients with high CDKN2A expression were at a higher risk of developing cancer (C) and had a shorter progression-free survival time (D)

Fig. 9

Underlying signaling pathways (Kyoto Encyclopedia of Genes and Genomes) of CDKN2A in a variety of tumors