Genetic Variants in Cell Cycle Control Pathway Confer Susceptibility to Lung Cancer

Abstract

Purpose: To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition. Experimental Design: We explored lung cancer risk associations of 11polymorphisms in seven cell cycle genes in a large case-control study including 1,518 Caucasian lung cancer patients and 1,518 controls. Results: When individuals with variant-containing genotypes were compared with homozygous wild-type carriers, a significantly increased lung cancer risk was identified for polymorphisms in p53 intron 6 [rs1625895; odds ratio (OR), 1.29; 95% confidence interval (95% CI), 1.08-1.55] and in p27 5 ¶ untranslated region (UTR; rs34330; OR, 1.27; 95% CI, 1.01-1.60). Compared with homozygous wild-types, the homozygous variant genotypes of STK15 F31I and CCND1 G870A were associated with a significantly altered lung cancer risk with ORs of 0.58 (95 % CI, 0.37-0.90) and 1.26 (95% CI, 1.03-1.53), respectively. To assess the cumulative effects of all the investigated polymorphisms on lung carcinogenesis, we conducted a combined analysis and found that compared with low-risk individuals with few adverse alleles, individuals with more adverse alleles had an increased risk in a significant dose-dependent manner (P trend = 0.041). This pattern was more evident in ever smokers (P trend = 0.037), heavy smokers (P trend = 0.020), and older subjects (P trend = 0.011). Higher-order gene-gene interactions were evaluated using the classification and regression tree analysis, which indicated that STK15 F31I and p53 intron 6 polymorphisms might be associated with lung carcinogenesis in never/light-smokers and heavy smokers, respectively. Conclusions: Our results suggest that cell cycle gene polymorphisms and smoking may function collectively to modulate the risk of lung cancer.

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

“…Within the 1‐kb region surrounding CDKN1B , six SNPs resulted to be nominal significant ( P ≤ 0.05). Interestingly, the T allele of rs34330, which maps to the CDKN1B promoter region (‐79 C/T), has been reported to be associated with other tumours including breast 26, endometrial 27, lung 28 and thyroid cancer and with low gene expression of CDKN1B 29. Together, these data led us to exclude other SNPs from further analyses, and to focus our attention on rs34330 ( P = 0.015; OR = 1.15).…”

“…The association of the SNP rs34330 has been found in diverse tumours 26, 27, 28. Particularly, Landa et al .…”

Polymorphisms of cancer-related genes and risk of multipleprimary malignancies involving colorectal cancer

“…Five of these loci were previously reported to have variable association with the risk of single primary colorectal cancer; rs1061624 of TNFRSF1B, rs1059234 of P21, and rs9344 of CCND1 were found to reduce the risk of colorectal cancer and exert protective effects, while rs28362491 of NFKB1 and rs3212986 of ERCC1 increased the risk of colorectal cancer. Among the other 30 loci, five (rs7566, rs887574, rs13035, rs1799757, and rs5343) are reported for the first time in this study, while 25 were associated with malignant tumor development and the response to chemoradiotherapy (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), inflammatory bowel disease (34), autoimmune diseases (35,36), vitiligo (37), insulin resistance (38), coronary heart disease, stroke, and other types of cardiovascular and cerebrovascular disease (39,40).…”

Effects of the Cyclin D1 Polymorphism on Lung Cancer Risk - a Meta-analysis

“…A total of 10 case-control studies with a total of 10, 548 subjects on the association between CCND1 G870A polymorphism and lung cancer risk were included for this meta-analysis (Qiuling et al, 2003;Wang et al, 2003;Buch et al, 2005;Gautschi et al, 2006;Hung et al, 2006;Sobti et al, 2006;Wang et al, 2007;Wang et al, 2008;Li et al, 2009;Hsia et al, 2011). There were four studies of European population (Buch et al, 2005;Gautschi et al, 2006;Hung et al, 2006;Wang et al, 2007), five studies of Asians (Qiuling et al, 2003;Wang et al, 2003;Wang et al, 2008;Li et al, 2009;Hsia et al, 2011) and one study of mixed population (Sobti et al, 2006).…”

“…There were four studies of European population (Buch et al, 2005;Gautschi et al, 2006;Hung et al, 2006;Wang et al, 2007), five studies of Asians (Qiuling et al, 2003;Wang et al, 2003;Wang et al, 2008;Li et al, 2009;Hsia et al, 2011) and one study of mixed population (Sobti et al, 2006). There were about 80.0% studies using the classic PCR-RFLP assay to genotype the CCND1 G870A polymorphism.…”