Novel genetic variants in genes of the Fc gamma receptor-mediated phagocytosis pathway predict non-small cell lung cancer survival

Danwen Qian; Hongliang Liu; Lingling Zhao; Xiaomeng Wang; Sheng Luo; Patricia G Moorman; Edward F Patz Jr; Li Su; Sipeng Shen; David C Christiani; Qingyi Wei

doi:10.21037/tlcr-19-318

Novel genetic variants in genes of the Fc gamma receptor-mediated phagocytosis pathway predict non-small cell lung cancer survival

Transl Lung Cancer Res. 2020 Jun;9(3):575-586. doi: 10.21037/tlcr-19-318.

Authors

Danwen Qian^{1

2

3}, Hongliang Liu^{2

3}, Lingling Zhao^{2

3}, Xiaomeng Wang^{2

3}, Sheng Luo⁴, Patricia G Moorman^{2

5}, Edward F Patz Jr^{2

6}, Li Su⁷, Sipeng Shen⁷, David C Christiani^{7

8}, Qingyi Wei^{2

3

9}

Affiliations

¹ Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, 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 Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
⁵ Department of Family Medicine and Community Health, Duke University School of Medicine, Durham, NC, USA.
⁶ Department of Radiology, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
⁷ Department of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
⁸ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Abstract

Background: Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC).

Methods: We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients.

Results: In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs (PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10^-4] and 1.18 (95% CI: 1.08-1.29 and 1.32×10^-4, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10^-5). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues.

Conclusions: Genetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted.

Keywords: Fc gamma receptor (FCGR); Non-small cell lung cancer (NSCLC); genome-wide association study (GWAS); single-nucleotide polymorphism (SNP); survival.

Abstract

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