Genetic Variations of CD40 and LTβR Genes Are Associated With Increased Susceptibility and Clinical Outcome of Non-Small-Cell Carcinoma Patients

Foteinos-Ioannis D Dimitrakopoulos; Anna G Antonacopoulou; Anastasia E Kottorou; Melpomeni Kalofonou; Nikolaos Panagopoulos; Dimitrios Dougenis; Thomas Makatsoris; Vasiliki Tzelepi; Angelos Koutras; Haralabos P Kalofonos

doi:10.3389/fonc.2021.721577

Genetic Variations of CD40 and LTβR Genes Are Associated With Increased Susceptibility and Clinical Outcome of Non-Small-Cell Carcinoma Patients

Front Oncol. 2021 Sep 17:11:721577. doi: 10.3389/fonc.2021.721577. eCollection 2021.

Affiliations

¹ Division of Oncology, Department of Medicine, University of Patras, Patras, Greece.
² Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, Greece.
³ Centre for Bio-Inspired Technology, Institute of Biomedical Engineering, Imperial College London, London, United Kingdom.
⁴ Department of Cardiothoracic Surgery, University of Patras, Patras, Greece.
⁵ Department of Pathology, University of Patras, Patras, Greece.

Abstract

Background: Immune system-related receptors CD40 (tumor necrosis factor receptor superfamily member 5), BAFFR (tumor necrosis factor receptor superfamily member 13C), and LTβR (tumor necrosis factor receptor superfamily member 3) play a pivotal role in non-small-cell lung cancer (NSCLC). To further evaluate their role in NSCLC, CD40 rs1883832 (T>C), BAFFR rs7290134 (A>G), and LTβR rs10849448 (A>G) single-nucleotide polymorphisms (SNPs) were investigated regarding their impact in risk and clinical outcome of NSCLC patients.

Methods: The three selected SNPs were evaluated in 229 NSCLC patients and 299 healthy controls, while CD40, BAFFR, and LTβR protein expression was assessed by immunohistochemistry in 96 tumor specimens from NSCLC patients.

Results: In total, CD40 rs1883832 was associated with NSCLC risk, with the T allele, after adjusting for cofactors, being related to increased risk (p = 0.007; OR 1.701). Moreover, the CT genotype was associated with increased risk (p = 0.024; OR 1.606) and poorer 5-year overall survival (OS) after adjusting for cofactors (p = 0.001, HR 1.829), while CC was associated with higher CD40 expression in tumorous cells (p = 0.040) and in stromal cells (p = 0.036). In addition, AA homozygotes for the LTβR rs10849448 had increased risk for NSCLC in multivariate analysis (p = 0.008; OR, 2.106) and higher LTβR membranous expression (p = 0.035). Although BAFFR rs7290134 was associated with BAFFR membranous expression (p = 0.039), BAFFR rs7290134 was not associated with neither the disease risk nor the prognosis of NSCLC patients.

Conclusions: In conclusion, CD40 rs1883832 and LTβR rs10849448 seem to be associated with increased risk for NSCLC, while CD40 rs1883832 is also associated with OS of patients with NSCLC.

Keywords: NSCLC; SNP; prognosis; risk; rs10849448; rs1883832; rs7290134.