Abstract 110P
Background
Transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids, which plays an important role in the control of tumor growth and progression in human cancers. However, previous studies have not investigated the associations between genetic variants of the transsulfuration pathway genes and survival in patients with non-small cell lung cancer (NSCLC). Besides, the roles of functional genetic variants of the transsulfuration pathway genes and their functionality involved in tumor growth and progression are still unclear.
Methods
We first evaluate associations between genetic variants of 4,966 single-nucleotide polymorphisms (SNPs) in 55 transsulfuration pathway genes and survival of 1,185 NSCLC patients from PLCO Cancer Screening Trial, and then we validated the results with 984 NSCLC patients in the GWAS dataset from the HLCS Study. Furthermore, functional analyses were performed by expression quantitative trail loci (eQTL) and CRISPR-Cas9-mediated gene knockout (KO) to explore the role of CBS in vitro and in vivo models of NSCLC.
Results
We identified that CBS rs112335247 and COMT rs174699 were significantly associated with NSCLC OS with a combined HR of 0.76 and 1.38, respectively. Further eQTL analysis showed significant associations between these genotypes and mRNA expression levels. And then, CBS expression was knocked out in A549 and H1299 cells. As expected, we found that the proliferation of A549 and H1299 cells with CBS-KO showed a significant slowdown (P < 0.05), compared to that A549 and H1299 control cells, which indicated that CBS had a higher proliferation potential. Moreover, our results showed that A549 CBS-KO and H1299 CBS-KO cells possessed significantly less migration and invasion capacities in vivo. Finally, our results revealed that CBS-KO markedly inhibited cell proliferation, colony formation and invasion in the NSCLC cell lines and significantly delayed tumor growth in mice.
Conclusions
The genetic variants of the CBS rs112335247 and COMT rs174699 might be predictors of survival of NSCLC patients; and CBS plays an oncogenic role in lung cancer, which could be used as a potential therapeutic target for drug development.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Henan Cancer Hospital.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.