Single nucleotide polymorphisms in FOXP1 and RORA of the lymphocyte activation-related pathway affect survival of lung cancer patients

Hailei Du; Rui Mu; Lihua Liu; Hongliang Liu; Sheng Luo; Edward F Patz Jr; Carolyn Glass; Li Su; Mulong Du; David C Christiani; Hecheng Li; Qingyi Wei

doi:10.21037/tlcr-22-104

Single nucleotide polymorphisms in FOXP1 and RORA of the lymphocyte activation-related pathway affect survival of lung cancer patients

Transl Lung Cancer Res. 2022 May;11(5):890-901. doi: 10.21037/tlcr-22-104.

Authors

Hailei Du^{1

2

3}, Rui Mu^{2

3}, Lihua Liu^{2

3

4}, Hongliang Liu^{2

3}, Sheng Luo⁵, Edward F Patz Jr^{2

6}, Carolyn Glass^{2

7}, Li Su⁸, Mulong Du⁸, David C Christiani^{8

9}, Hecheng Li¹, Qingyi Wei^{2

3

10

11}

Affiliations

¹ Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
³ Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.
⁴ Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁵ Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
⁶ Departments of Radiology, Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
⁷ Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
⁸ Departments of Environmental Health and Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
¹¹ Duke Global Health Institute, Duke University, Durham, NC, USA.

Abstract

Background: Lymphocyte activation is part of a complex microenvironment that affects the development and progression of solid tumors. The present study analyzed the associations between genetic variants in lymphocyte activation-related genes and survival of patients with non-small cell lung cancer (NSCLC).

Methods: Our study evaluated the associations of 14,400 (1,599 genotyped and 12,801 imputed) single-nucleotide polymorphisms (SNPs) in 176 lymphocyte activation pathway-related genes with survival of 1,185 NSCLC patients in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 984 NSCLC patients from the Harvard Lung Cancer Susceptibility (HLCS) trial.

Results: Multivariable Cox proportional hazards regression analyses identified two distinct and possibly functional variants in forkhead box P1 (FOXP1; rs2568847 G>C) and RAR-related orphan receptor A (RORA; rs922782 T>G) that were significantly and independently associated with overall survival (OS) [adjusted hazards ratios (HRs) of 1.21 and 0.82, respectively; 95% confidence intervals (CI), 1.11 to 1.32 and 0.76 to 0.88, respectively; P=5.38×10^-6 and 2.68×10^-2, respectively]. Combined analysis of the unfavorable genotypes showed a significant correlation with both OS and disease-specific survival (DSS) in patients with NSCLC patients from PLCO trial (both P_trend<0.0001). Further expression quantitative trait loci (eQTL) analysis using RORA mRNA expression and genotype data in the 1000 Genomes Project demonstrated that the RORA rs922782 G allele predicted mRNA expression levels.

Conclusions: Genetic variants in FOXP1 and RORA of the lymphocyte activation pathway may be promising predictors of NSCLC survival. The RORA rs922782 G allele may predict NSCLC survival, possibly by controlling RORA mRNA expression.

Keywords: Non-small cell lung cancer (NSCLC); lymphocyte activation; single-nucleotide polymorphism; survival.

Abstract

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