Significant Association between Polymorphisms of Wnt Antagonist Genes and Lung Cancer

Abstract

Further elucidation of the molecular mechanisms underlying lung cancer (LC) is essential for the development of new effective therapeutic agents. Recently, involvement of Wnt antagonists in oncogenesis has been demonstrated in several cancers. The investigation of their contribution to lung carcinogenesis is still under investigation. We aimed to investigate whether there is a susceptibility or preventive effect of Wnt antagonist gene polymorphisms on the development and/or prognosis of LC. We investigated 110 LC patients and 160 controls. Single-nucleotide polymorphisms of Wnt antagonist genes including DKK2 (rs17037102), DKK3 (rs3206824), DKK3 intron4 G/C (rs7396187), DKK4 (rs2073664), and sFRP4 (rs1802074) were analyzed using nested polymerase chain reaction and restriction fragment length polymorphism. Results showed that patients with DKK3 AA compared with controls have a decreased risk of LC (adjusted for smoking habit, body mass index, and familial history) (P = 0.02; odds ratio [OR],0.08; 95% confidence interval [95% CI], 0.01-0.7). It was found that, for sFRP4 polymorphism, patients with GG and GA genotypes versus AA genotype controls showed a decreased risk for LC (P = 0.01; [OR, 0.19; 95% CI, 0.05-0.73 for GG genotype]; [OR = 0.18, 95% CI, 0.04-0.72 for GA genotype]). In addition, a decreased risk of LC was also found for the genotype combination of DKK3 (rs3206824) GG and sFRP4 AG + GG (P = 0.004; OR, 0.12; 95% CI, 0.02-0.58). We suggest that these 2 polymorphisms have a protective effect on LC in this study.

Gene-gene Interaction of AhR With and Within the Wnt Cascade Affects Susceptibility to Lung Cancer

“…characterised by DKK2 (rs17037102 / rs419558) and Axin2 (rs9915936). A similar picture was observed in a sample of 270 subjects from Istanbul, Turkey [23].…”

“…We failed to directly replicate the single marker associations reported by Bahl et al [21,22] (North India) and Yilmaz et al [23] (Turkey). The Indian population is known to be a mixture of several subpopulations [40], which can result in spurious associations.…”

“…characterised by DKK2 (rs17037102 / rs419558) and Axin2 (rs9915936). A similar picture was observed in a sample of 270 subjects from Istanbul, Turkey [23]. A two-way interaction between DKK3 (rs3206824) and SFRP4 (rs1802074) was found to be predictive of LC.…”

“…For this investigation we extracted the genotypes of 113 genomic variants (markers) assigned to 58 genes, previously reported as associated to LC or one of its histological subtypes [1][2][3][4][5][6][7][8] or proxies thereof (called LC-marker), and 296 markers assigned to 7 genes involved in Wnt signalling and listed in Bahl et al [21,22] and Yilmaz et al [23] (called AhR/Wnt-marker). Thus, we focused this analysis to genes previously investigated with respect to LC.…”

A natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis

“…29 ) concomitant with WNT pathway activation 30 . Intriguingly, allelic variants of DKK3, which is implicated in WNT signalling control, have been associated with predisposition to renal cell carcinoma 31 and squamous lung carcinoma 32 as well. Furthermore, both p15 Ink4b and CDK6 are critically implicated in the regulation of hematopoietic stem cell fate in mouse and man 33–35 .…”