Influence of the KDM4A rs586339 polymorphism on overall survival in Asian non-small-cell lung cancer patients

Abstract

The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1.68, P=0.042). In the current study, we investigated the association between the same polymorphism with OS in our Asian NSCLC-adenocarcinoma patients comprising Chinese (N=572), Malays (N=50), and Indians (N=22). KDM4A SNP-A482 genotype status was determined by Sanger sequencing. OS was calculated from the date of diagnosis to date of death or censored at the date of last follow-up. Kaplan-Meier analysis, log-rank test, and Cox regression methods were utilized to evaluate OS outcomes. KDM4A SNP-A482 had a minor allele (C) frequency of 18.8% and a major allele (A) frequency of 81.2% in our Asian NSCLC (adenocarcinoma) patients. However, the OS in our Asian NSCLC patients homozygous for KDM4A SNP-A482 was not significantly different from those who were wild type or heterozygous at this locus [CC vs. AA/AC: median OS (95% confidence interval): 40.2 (18.7-61.6) vs. 29.6 (26.9-32.3) months; P=0.858]. The results remained statistically nonsignificant even after adjustment for epidermal growth factor receptor mutational status, suggesting that KDM4A SNP-A482 does not significantly influence OS in Asian NSCLC patients.

The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities

“… 54 KDM4A is aberrantly expressed in lung carcinoma and mediates tumorigenesis by modulating the transformation, proliferation, invasion, and metastasis of cancer cells. 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 In the human lung cancer cell line A549, KDM5A collaborates with oncogenic K-Ras to promote cellular transformation by down-regulating tumor suppressor chromodomain helicase DNA binding protein 5 (CHD5), 63 a gene activating p53 signaling by targeting p19ARF and impeding p53 ubiquitination degradation. 64 Knockout of KDM4A from K-Ras-activated A549 cells triggers the senescence of cancer cells.…”

Advances in histone demethylase KDM4 as cancer therapeutic targets

“…North American NSCLC patients homozygous for the KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) have significantly lower overall survival (OS) than patients harboring the wild-type allele. 61 In addition, mTOR inhibitors reduce KDN4A SNP-A482 protein expression and concomitantly increase anticancer drug sensitivity. 62 However, KDM4A SNP-A482 has no significant effect on OS in Asian NSCLC patients.…”

“…These effects are KDM4A‐dependent as SIRT2 binds to the promoter region of KDM4A and negatively regulates KDM4A expression in NSCLC. North American NSCLC patients homozygous for the KDM4A single nucleotide polymorphism (SNP)‐A482 (rs586339) have significantly lower overall survival (OS) than patients harboring the wild‐type allele . In addition, mTOR inhibitors reduce KDN4A SNP‐A482 protein expression and concomitantly increase anticancer drug sensitivity .…”