Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways

Abstract

The DNA repair systems maintain the integrity of the human genome and cell cycle checkpoints are a critical component of the cellular response to DNA damage. We hypothesized that genetic variants in DNA repair and cell cycle control pathways will influence the predisposition to lung cancer, and studied 27 variants in 17 DNA repair enzymes and 10 variants in eight cell cycle control genes in 1,604 lung cancer patients and 2,053 controls. To improve the estimation of risks for specific variants, we applied a Bayesian approach in which we allowed the prior knowledge regarding the evolutionary biology and physicochemical properties of the variant to be incorporated into the hierarchical model. Based on the estimation from the hierarchical modeling, subjects who carried OGG1 326C/326C homozygotes, MGMT 143V or 178R, and CHEK2 157I had an odds ratio of lung cancer equal to 1.45 [95% confidence interval (95% CI), 1.05-2.00], 1.18 (95% CI, 1.01-1.40), and 1.58 (95% CI, 1.14-2.17). The association of CHEK2 157I seems to be overestimated in the conventional analysis. Nevertheless, this association seems to be robust in the hierarchical modeling. None of the pathways seem to have a prominent effect. In general, our study supports the notion that sequence variation may explain at least some of the variation of inherited susceptibility. In particular, further investigation of OGG1, MGMT, and CHEK2 focusing on the genetic regions where the present markers are located or the haplotype blocks tightly linked with these markers might be warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2736 -44)

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

“…Other variants in CHEK2 have been associated with lung cancer risk, but a possible association of 1100delC with lung cancer risk had never been investigated before. [26][27][28][29][30][31] Thus, we examined whether the 1100delC variant is associated with lung cancer risk by investigating a prevalent cohort of 457 lung cancer patients. Of these, 449 were homozygous wild type and 4 were heterozygous for the 1100delC mutation; no 1100delC homozygous patients were found (genotyping failed repeatedly for the remaining four patients).…”

“…[22][23][24][25] Other variants in CHEK2 have been associated with lung cancer, but a possible association of 1100delC with lung cancer has never been investigated. [26][27][28][29][30][31] Homozygosity for 1100delC is expected to be rare, and until recently, there had only been two reports on homozygous carriers, a male who developed colon cancer at age 52 years 32 and a female who developed bilateral breast cancer at ages 47 and 61 years and uterine sarcoma at age 58 years. 33 Recently, Adank et al 34 reported 12 homozygous 1100delC mutation carriers from 8 breast cancer families from the Netherlands.…”

ΔN133p53 expression levels in relation to haplotypes of the TP53 internal promoter region

“…Another common polymorphism is the 16 base pair (bp) duplication within intron 3 of the TP53gene (rs17878362). This polymorphism was shown to be a modifier in breast cancer disease both in its sporadic and familial forms [Costa et al, 2008;Pim and Banks, 2004], and was associated with an increased risk of gastric [Kim et al, 2007], breast [Buyru et al, 2007;Costa et al, 2008], head and neck [Mitra et al, 2003], lung [Hung et al, 2007], and colorectal cancer and with reduced basal levels of TP53 mRNA in EBV immortalized lymphoblastoid cell lines [Gemignani et al, 2004]. The incomplete linkage disequilibrium between p.Arg72Pro and PIN3 underlies the possibility that all these findings are independent observations, implying that there is more to understand about biology of TP53.…”

Repair System of 7, 8-Dihydro-8-Oxoguanine as a Defense Line against Carcinogenesis

“…48) Hung et al suggested that sequence variants in CHEK2, MGMT, and OGG1 were positively associated with lung cancer risk. 49) To understand the OGG1 function associated with cancer, polymorphism studies are a useful strategy. Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; thus, a deficiency in repair capacity may lead to genetic instability and carcinogenesis.…”