Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes

Abstract

Laryngeal cancer is known to be associated with smoking and high alcohol consumption. Nucleotide excision repair (NER) plays a key role in repairing DNA damage induced by these exposures and might affect laryngeal cancer susceptibility. In a populationbased case-control study including 248 cases and 647 controls, the association of laryngeal cancer with 14 single nucleotide polymorphisms (SNPs) in 8 NER genes (XPC, XPA, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. For genotyping, sequence specific hybridization probes were used. Data were evaluated by conditional logistic regression analysis, stratified for age and gender, and adjusted for smoking, alcohol consumption and education. Pro-carriers of ERCC6 Arg1230Pro showed a decreased risk for laryngeal cancer (OR 5 0.53, 95% CI 0.34-0.85), strongest in heavy smokers and high alcohol consumers. ERCC5 Asp1104His was associated with risk in heavy smokers (OR 5 1.70, 95% CI 1.1-2.5). Val-carriers of RAD23B Ala249Val had an increased cancer risk in heavy smokers (OR 5 1.6, 95% CI 1.1-2.5) and high alcohol consumers (OR 5 2.0, 95% CI 1.1-3.4). The combined effect of smoking and alcohol intake affected risk, at high exposure level, for ERCC6 1230Pro carriers (OR 5 0.47, 95% CI 0.22-0.98) and RAD23B 249Val carriers (OR 5 2.6, 95% CI 1.3-4.9). When tested for gene-gene interaction, presence of 3 risk alleles in the XPC-RAD23B complex increased the risk 2.1-fold. SNPs in the other genes did not show a significant association with laryngeal cancer risk. We conclude that common genetic variations in NER genes can significantly modify laryngeal cancer risk. ' UICCKey words: genetic variation; population-based case-control study; haplotype; cancer susceptibility; gene-environment interaction Laryngeal cancer is the most frequent form of head and neck cancers in Germany and the second most common form of respiratory tract cancers in the US. 1,2 The average age of onset of the disease is 64 years and it is more common in males than in females (6:1 ratio).Cigarette smoking and alcohol consumption are well acknowledged risk factors for laryngeal cancer. [3][4][5][6][7] Cancer risk is directly related with duration and number of cigarettes smoked, and considerably increased in individuals consuming more than 50 g of alcohol per day. Tobacco smoke contains many carcinogens including a group of N-nitrosamines that produce carcinogenic methyl and pyridyloxobutyl DNA adducts. 8 A further constituent of tobacco smoke is the highly toxic acetaldehyde 9,10 which produces genotoxic 1,N 2 -propano-2 0 -deoxyguanosine DNA adducts. 9,11 Acetaldehyde is also an intermediate product of ethanol metabolism and its concentration increases in a multiplicative manner in individuals who are simultaneously smoking and drinking alcohol. 12 This observation might explain the synergistic and multiplicative effect found for alcohol and smoking in laryngeal cancer risk. 3,7 DNA repair is of fundamental importance in maintaining genomic stabilit...

Genetic polymorphisms in key DNA repair genes and risk of head and neck cancer in a Chinese population

“…There have been several studies showing associations between this SNP and risk of multiple cancers, including HNC, but the results from different populations were confusing rather than conclusive (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Recently, a meta-analysis with a total of 12 studies claimed that the XPD Lys751Gln polymorphism was not associated with HNC risk (17); however, no genotyping data from the Chinese population was included, with the exception of a Taiwan study with a small sample size of 154 cases and 105 controls (30).…”

“…The His1104Asp polymorphism (rs17655), located in exon 15 of XPG, has been largely investigated in studies on susceptibility to cancers of the breast (44), lung (45), stomach (46), bladder (47), colorectum (48) and head and neck (18,36,49,50). Although it was reported that the His1104Asp polymorphism of XPG together with SNPs of several other NER genes jointly contributed to the variability of DRC (16), we found that the His1104Asp polymorphism was not associated with the risk of HNC in China, supporting the results from other published studies for this SNP and HNC risk (18,36,49,50).…”

A genetic view of laryngeal cancer heterogeneity

“…In particular, ERCC6 showed a decreased risk, while ERCC5 and RAD23B increased it. 24 Furthermore, XPD and ERCC1 may be associated to poor disease free survival (DFS) in SCCHN, suggesting a significant role of NER in these tumors. 25 …”

Associations of ERCC4 rs1800067 Polymorphism with Cancer Risk: an Updated Meta-analysis

“…Four publications were excluded because of meta-analysis, control group had cancer patients or not published in English. Finally, 26 full-text articles with eligibility were included in this meta-analysis (Smith et al, 2003;Huang et al, 2006;Mechanic et al, 2006;Moreno et al, 2006;Crew et al, 2007;Jorgensen et al, 2007;Chang et al, 2008;Hung et al, 2008;McWilliams et al, 2008;Rajaraman et al, 2008;Abbasi et al, 2009;Han et al, 2009;Joshi et al, 2009;Agalliu et al, 2010;Rajaraman et al, 2010;Doherty et al, 2011;Krupa et al, 2011;Smith et al, 2011;Gil et al, 2012;Yu et al, 2012;Cheng et al, 2013;Santos et al, 2013;Wang et al, 2013;Wyss et al, 2013;Kohlhase et al, 2014;Steck et al, 2014). The flow chart which reflected the details of article selection was presented in Figure 1.…”