A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival

Abstract

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819TNS3 at 7p12.3 (P = 3.90 × 10−9) and rs1143149SEPT7 at 7p14.2 (P = 9.75 × 10−9), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819TNS3: Pinteraction = 8.0 × 10−4; rs1143149SEPT7: Pinteraction = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.

ATHENA: an independently validated autophagy-related epigenetic prognostic prediction model of head and neck squamous cell carcinoma

“…Gene–environment and gene–gene interactions provided additional insights into the biological mechanisms of complex diseases [ 31 – 33 ]. In our previous study [ 34 ], we explored epigenome-wide gene–age interaction and significantly improved the accuracy of prognostic prediction model of oral squamous cell carcinoma.…”

Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma

“…We found that carriers of two polymorphic SEPTIN7 rs3801339 alleles had shorter PFS from diagnosis, even after adjusting for clinical factors. Septin 7 is a GTP-binding protein that plays an important role in various cellular processes [ 14 , 33 ]. Its binding to the CALB2 promoter region resulted in decreased calretinin expression in MM cell lines [ 14 ].…”

Lyz2-Cre-Mediated Genetic Deletion of Septin7 Reveals a Role of Septins in Macrophage Cytokinesis and Kras-Driven Tumorigenesis

“…Another possibility is that the appearance of this novel (non-adenoma) tumor cells is caused by Kras activation combined with genetic instability caused by the loss of Septin7. Interestingly, a recent multi-omics study correlated low SEPTIN7 expression levels and an intronic single-nucleotide polymorphism in the SEPTIN7 gene with higher survival rates for long-term former smoking lung cancer patients ( Shen et al, 2021 ). While the presence of Septin7 seems indispensable for oncogenic Ras-induced lung-adenocarcinoma formation, further investigations in the Septin7 conditional knockout model is necessary to completely understand the role of septins in tumorigenesis.…”