Systematic evaluation of genetic variants in three biological pathways on patient survival in low-stage non-small cell lung cancer

Abstract

Introduction: Studies from selected candidate genes suggest that single-nucleotide polymorphisms (SNPs) involved in glutathione metabolism, DNA repair, or inflammatory responses may affect overall survival (OS) in stages I to II or low-stage non-small cell lung cancer (LS-NSCLC); however, results are inconclusive. In this study, we took a systematic pathway-based approach to simultaneously evaluate the impact of genetic variation from these three pathways on OS after LS-NSCLC diagnosis.

Methods: DNA from 647 patients with LS-NSCLC was genotyped for 480 SNPs (tag-SNPs) tagging 57 genes from the three candidate pathways. Associations of tag-SNPs with OS were assessed at the individual SNP and whole gene levels, adjusting for age, tumor stage, surgery type, and adjuvant therapy. The genotype combinations of the SNPs associated with OS were also estimated.

Results: Among the 412 tag-SNPs that were successfully genotyped and passed quality assessments, 28 showed association with OS (p < 0.05). Two of the 28 were estimated to have less than a 20% chance of being false positives (rs3768490 in GSTM5: p = 1.32 × 10, q = 0.06; rs1729786 in ABCC4: p = 9.25 × 10, q = 0.20). Gene-based analysis suggested that in addition to GSTM5 and ABCC4, variation in two other genes, PTGS2 and GSTA2, was also associated with OS.

Conclusions: We describe further evidence that variations in genes involved in the glutathione and inflammatory response pathways are associated with OS in patients with LS-NSCLC. Further studies are warranted to verify our findings and elucidate their functional mechanisms and clinical utility leading to improved survival for patients with lung cancer.

Figure 1. Adjusted survival curves for the nine combinations of the top two SNP genotypes

Each line represents one of the nine genotype combinations between rs3768490 and rs1729786. Average method was used for the multivariate adjusted curves. The black line (CC/GG of rs3768490 and rs1729786) was the reference group used for statistical testing of significance. Survival probability from 0 to 0.5 on y-axis was cut for better readability of the curves and survival time was truncated at 5 years post diagnosis.

Figure 2. Adjusted survival curves by composite risk scores

Adjusted survival curves were created for the patients with risk scores of 0/1, 2, 3, and 4 using average method. The adjusted variables included age at diagnosis, lung cancer stage, surgery subtype, and adjuvant therapy. Patients with a score of 0 were not statistically different from those with a score of 1 and the two groups were therefore combined and used as reference (black line). Survival probability from 0 to 0.5 on y-axis was cut for better readability of the curves and survival time was truncated at 5 years post diagnosis. .