A nonsynonymous polymorphism in IL23R gene is associated with risk of gastric cancer in a Chinese population

Interleukin‐23 receptor (IL‐23R) is a key element in T helper (Th)17 cell‐mediated inflammatory process, which plays an important role in pathogenesis of gastric cancer. Genetic variants of IL‐23R have been identified as the predisposing factors for immunopathologic process. In this study, we hypothesized that the functional genetic variants of IL‐23R gene may modify the risk of gastric cancer. To test this hypothesis, we conducted a case–control study including 1043 gastric cancer patients and 1089 controls in a Chinese population to assess the association between two potentially functional single nucleotide polymorphisms (SNPs) rs6682925 T>C and rs1884444 T>G of IL‐23R and risk of gastric cancer. We found that the variant allele (G) of rs1884444 T>G, with amino acid His substituted by Gln at codon 3, was significantly associated with a decreased risk of gastric cancer [adjusted allelic odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.88]. In the stratified analysis, we found that this protective effect of rs1884444 G allele was mainly evident in intestinal‐type gastric cancer (adjusted allelic OR = 0.75, 95% CI = 0.65–0.87) other than in diffuse‐type gastric cancer (adjusted allelic OR = 0.96, 95% CI = 0.76–1.22). However, we did not find any significant association of rs6682925 T>C with gastric cancer risk. These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T>G of IL‐23R may contribute to gastric cancer susceptibility, especially in intestinal‐type gastric cancer, in Chinese population. © 2010 Wiley‐Liss, Inc.     

Potentially functional polymorphisms in IL-23 receptor and risk of esophageal cancer in a Chinese population

Interleukin-23 (IL-23)/IL-23 receptor (IL-23R) is essential for Th17 cell-mediated immune response, involved in autoimmune diseases and cancer pathogenesis. Two potentially functional genetic single nucleotide polymorphisms (SNPs; IL-23R rs6682925 T>C and rs1884444 T>G) were found to contribute to cancer susceptibility. In our study, we conducted a case-control study including 1,645 patients with esophageal cancer and 1,694 cancer-free controls in a Chinese population to assess the association between the two SNPs and the risk of esophageal cancer. We found that IL-23R rs6682925 TC/CC and rs1884444 TG/GG variant genotypes were associated with significantly increased risk of esophageal cancer [rs1884444: adjusted odds ratio (OR) = 1.16, 95% confidence intervals (CIs) =1.01-1.33; rs6682925: adjusted OR = 1.23, 95% CIs = 1.07-1.42], compared to their corresponding wild-type homozygotes. Furthermore, the increased risks associated with the two SNPs were independent from smoking and alcohol drinking status. These findings indicated that genetic variants in IL-23R may contribute to esophageal cancer risk in our Chinese population.     

Nonsynonymous polymorphisms in FAT4 gene are associated with the risk of esophageal cancer in an Eastern Chinese population

FAT4 plays a crucial role in carcinogenesis as a key component of the Hippo signaling pathway. We hypothesized that potential functional polymorphisms in the FAT4 gene may modify the risk of esophageal cancer. To test this hypothesis, we evaluated the association between four nonsynonymous polymorphisms (rs1039808, rs12508222, rs1567047 and rs1014867) in FAT4 and esophageal cancer risk in a case–control study of 2,139 esophageal cancer cases and 2,273 controls in a Chinese population. We found that the T allele of rs1014867 (Pro4972Ser) was significantly associated with a decreased risk of esophageal cancer (odds ratio [OR]=0.77, 95% confidence interval [95% CI]=0.66–0.90; p=1.42 × 10^?3). We also observed a borderline significant association between rs1039808 (Ala807Val) and esophageal cancer risk (OR=0.90, 95% CI=0.82–1.00; p=0.050), which was more prominent in non‐drinkers (OR=0.82, 95% CI=0.71–0.94; p=6.53 × 10^?3). Furthermore, we detected a significant interaction between rs1039808 genotypes and alcohol drinking on esophageal cancer risk (p=0.013). These findings indicate that the nonsynonymous variants rs1014867 (Pro4972Ser) and rs1039808 (Ala807Val) of FAT4 may contribute to esophageal cancer susceptibility.     

Nucleotide variation in IL‐10 and IL‐12 and their receptors and cervical and vulvar cancer risk: A hybrid case–parent triad and case–control study

Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL‐12/IL‐10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case–parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log‐additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo‐likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3’ UTR SNP (OR=1.76, 95% CI=1.15–2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26–0.82; rs2229546, OR=0.43, 95% CI=0.21–0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26–3.96) and IL12RB1 rs11575934 non‐synonymous SNP (OR=1.51, 95% CI=1.12–2.05). Finally, the minor allele of the IL12B rs3181224 3’ UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12–0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.     

Association of HLA‐DRB1, interleukin‐6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population—A candidate gene approach

High‐risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case‐control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population‐based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL‐6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79–0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78–0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02–1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04–1.45 and OR = 1.29, 95% CI: 1.11–1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47–0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. © 2009 UICC     

Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer

Proinflammatory cytokines are associated with age-related diseases including arthritis and heart disease. IL6 and TNF also play key roles in estrogen modulation in older women. We explored whether variation in IL6 and TNF genes influenced the risk of breast cancer in samples that differed by age group: <44 years (228 cases and 271 controls), 45–64 years (426 cases and 396 controls), and 65+ years (228 cases and 239 controls). Samples were drawn from population-based case–control studies conducted in Seattle. Age-adjusted odds ratios (ORs) were calculated to evaluate the risk associated with variants in IL6, IL6R, TNF, and TNFRSF1A. There was a significantly increased risk of breast cancer associated with one or more C>T alleles at IL6 rs2069861 among subjects in the oldest age group (OR 1.8, 95% CI 1.1–2.9), but no overall increased risk of breast cancer associated with any IL6 or IL6R variants in the combined data. There were significantly elevated risks of breast cancer among women 45–64 years old associated with a UTR 5′ flanking SNP LTA rs2009658 C>G allele (OR 1.5, 95% CI 1.1–1.9) and a nonsynonomous coding SNP TNFRSF1A rs767455 T>C allele (OR 1.3, 95% CI 1.1–1.6); these two variants were also elevated in the combined data (OR 1.3, 95% CI 1.1–1.5 and OR 1.2, 95% CI 1.1–1.4, respectively). This study supports a modest association between a variant in IL6 and breast cancer among older women and TNF-related variants and breast cancer among middle-aged women. Further evaluation of these genes in other studies is warranted.     

Polymorphisms in prostate stem cell antigen gene rs2294008 increase gastric cancer risk in Chinese

A recent genome‐wide study identified a strong association between polymorphisms in the prostate stem cell antigen (PSCA) gene and the risk of diffuse‐type of gastric cancer in Japanese and Korean population. In this case–control study, we aimed to investigate the possible association between PSCA rs2294008 C/T with clinicopathological features and the prognosis of gastric cancer in a Southern Chinese population. Genotypes of 460 gastric cancer patients and 549 controls were determined by PCR‐restriction fragment length polymorphism (PCR‐RFLP) and DNA sequencing. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an increased risk for gastric cancer compared with CC genotype (OR = 1.42, 95% CI = 1.10–1.82, P = 0.006). Further stratification analyses indicated that the effect of PSCA rs2294008T carriers was noteworthy in intestinal type (OR = 1.55, 95% CI = 1.18–2.04, P = 0.002), poorly differentiated (OR = 1.59, 95% CI = 1.19–2.13, P = 0.002), noncardia (OR = 1.55, 95% CI = 1.17–2.04, P = 0.002) subtypes of gastric cancer. Cox proportional hazards analyses demonstrated that TT genotype (HR = 2.12, 95% CI = 1.22–3.69, P = 0.008) as well as TNM staging were prognostic factors of gastric cancer patients. In conclusion, The T allele of PSCA rs2294008 is associated with increased risk of gastric cancer, especially intestinal type, poorly differentiated, early onset, and noncardia gastric cancer in Chinese population. TNM staging and TT genotype might be involved in the prognosis of gastric cancer patients. Mol. Carcinog. © 2011 Wiley‐Liss, Inc.     

The PHLDB1 rs498872 (11q23.3) polymorphism and glioma risk: A meta‐analysis

The association between the rs498872 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta‐analysis. A comprehensive literature search was performed using PubMed and EMBASE database, with the last search up to August 23, 2013. Six articles including 10 case‐control studies in English with 18 002 controls and 8434 cases were eligible for the meta‐analysis. Subgroup analyses were conducted by source of controls and ethnicity. The combined results showed that rs498872 polymorphism was significantly associated with glioma risks (TT vs CC: OR = 1.337, 95% CI = 1.222–1.462; TC vs CC: OR = 1.173, 95% CI = 1.081–1.272; dominant model: OR = 1.199, 95% CI = 1.101–1.306; recessive model: OR = 1.237, 95% CI = 1.135–1.347; additive model: OR = 1.156, 95% CI = 1.085–1.232). Moreover, there was increased cancer risk in all genetic models after stratification of the SNP data by the source of controls and ethnicity, and no evidence of publication bias was produced. Our meta‐analysis suggested that rs498872 polymorphism was associated with increased risk of glioma. However, additional studies exploring the combined effects of rs498872 polymorphisms in Asian population should be investigated.     

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

In mammalian cells, X‐ray repair cross‐complementing group3 (XRCC3) plays an important role in the DNA double‐strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in the XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to gliomas. In this study, we used a haplotype‐based approach to investigate whether 4 tagging single nucleotide polymorphisms of the XRCC3 gene are associated with risk of gliomas in 771 glioma patients and 752 cancer‐free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, and haplotype associations were estimated using Haplo.Stat. After adjustment for age and sex, the variant G allele of rs861530 and T allele of rs3212092 were significantly associated with an increased risk of gliomas (AG/GG versus AA: adjusted OR = 1.44, 95% CI = 1.15–1.80, p = 0.001 and CT/TT versus CC: adjusted OR = 1.66, 95% CI = 1.12–2.46, p = 0.013, respectively). Consistent with these results, XRCC3 haplotype “GGCC” containing rs861530 G allele and haplotype “AGTC” containing rs3212092 T allele were also significantly associated with an elevated risk of gliomas compared with the common haplotype “AGCC” (adjusted OR = 1.35, 95% CI = 1.14–1.58, p = 0.000 and adjusted OR = 1.67, 95% CI = 1.11–2.52, p = 0.015, respectively). Our results suggest that common genetic variants in the XRCC3 gene may modulate glioma risk. © 2009 UICC     

Association of PSCA rs2294008 gene variants with poor prognosis and increased susceptibility to gastric cancer and decreased risk of duodenal ulcer disease

Two recent genome‐wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection‐related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR‐TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45–15.33] and nonsteroidal anti‐inflammatory drugs (OR: 6.54; 95% CI: 3.19–12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33–0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63–2.34), smoking (OR: 1.93; 95% CI: 1.54–2.61), family history of GC (OR: 2.83; 95% CI: 2.01–3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07–1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12–1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16–1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse‐type GC (hazard ratio: 1.85; 95% CI: 1.12–3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse‐type of GC in Caucasians.     

Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity

The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity (FP‐toxicity). Patients treated previously in a prospective study with fluoropyrimidine‐based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129‐5923C>G and c.1601G>A. The predictive value of MIR27A variants for early‐onset grade ≥3 FP‐toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random‐effects meta‐analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild‐type patients, MIR27A variants did not affect risk of FP‐toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87–1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP‐toxicity (OR 4.9, 95% CI: 1.24–19.7, p = 0.023). Rs11671784 was not associated with FP‐toxicity (OR 2.9, 95% CI: 0.47?18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP‐toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27–4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06?1.17, p = 0.081). In meta‐analysis, rs895819 remained significantly associated with FP‐toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83–15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP‐toxicity.     

<Emphasis Type="Italic">IL6</Emphasis> genotypes and colon and rectal cancer

Inflammation appears to play a key role in the development of colorectal cancer (CRC). In this study we examine factors involved in the regulation of inflammation and risk of CRC. Data from a multi-center case–control study of colon (N = 1579 cases and N = 1977 controls) and rectal (N = 794 cases and N = 1005 controls) cancer were used to evaluate the association between the rs1800795 and rs1800796 IL6 polymorphisms and CRC. We evaluated the joint effects of IL6 single nucleotide polymorphisms and regular use of aspirin/NSAIDs and vitamin D receptor (VDR) genotype. Having a C allele of the rs1800796 IL6 polymorphisms and the GG genotype of the rs1800795 IL6 polymorphisms was associated with a statistically significantly reduced the risk of colon (OR 0.76 95% CI 0.57, 1.00), but not rectal (OR 1.49 95% CI 1.02,2.16) cancer. Both IL6 polymorphisms were associated with significant interaction with current use of aspirin/NSAIDs to alter risk of colon cancer: individuals with a C allele in either polymorphism who were current users of aspirin/NSAIDs had the lowest colon cancer risk. CRC risk also was associated with an interaction between VDR and IL6 genotypes that was modified by current use of aspirin/NSAIDs. This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways.     

Vitamin D receptor rs2228570 polymorphism and invasive ovarian carcinoma risk: Pooled analysis in five studies within the Ovarian Cancer Association Consortium

The association of invasive ovarian carcinoma risk with the functional polymorphism rs2228570 (aka rs10735810; FokI polymorphism) in the vitamin D receptor (VDR) gene was examined in 1820 white non‐Hispanic cases and 3479 controls in a pooled analysis of five population‐based case–control studies within the Ovarian Cancer Association Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Carriers of the rare T allele were at increased risk of ovarian carcinoma compared to women with the CC genotype in all studies combined; each copy of the T allele was associated with a modest 9% increased risk (OR = 1.09; 95% CI: 1.01–1.19; p = 0.04). No significant heterogeneity among studies was observed (p = 0.37) and, after excluding the dataset from the Hawaii study, the risk association for rs2228570 among replication studies was unchanged (OR = 1.09; 95% CI: 1.00–1.19; p = 0.06). A stronger association of rs2228570 with risk was observed among younger women (aged < 50 years versus 50 years or older) (p = 0.04). In all studies combined, the increased risk per copy of the T allele among younger women was 24% (OR = 1.24; 95% CI: 1.04–1.47; p = 0.02). This association remained statistically significant after excluding the Hawaii data (OR = 1.20; 95% CI: 1.01–1.43; p = 0.04). No heterogeneity of the association was observed by stage (p = 0.46), tumor histology (p = 0.98), or time between diagnosis and interview (p = 0.94). This pooled analysis provides further evidence that the VDR rs2228570 polymorphism might influence ovarian cancer susceptibility.     

IL12 polymorphisms,HBV infection and risk of hepatocellular carcinoma in a high‐risk Chinese population

To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3′UTR G>A), rs2243115 (5′UTR T>G) in IL12A and rs3212227 (3′UTR A>C) in IL12B in a case–control study of 869 hepatocellular carcinoma (HCC) cases and 891 cancer‐free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.17–2.00), compared with the wild‐type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR = 1.71, 95% CI = 1.23–2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.     

Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract

Objectives The purpose of this study was to investigate the role of polymorphisms of genes involved in inflammation in the risk of cancers of the upper aerodigestive tract (UADT). Methods We have evaluated the role of polymorphisms in key genes related to inflammation, namely IL1B (rs1143627), COX2/PTGS2 (rs5275), and IL8 (rs4073) in a large case–control study comprising 811 UADT cancer cases and 1,083 controls. Results An association was observed for squamous cell carcinoma of the pharynx for a polymorphism in the promoter of the IL1B gene, with an OR of 2.39 (95% CI = 1.19–4.81) for the homozygotes for the minor allele A promoter polymorphism of IL8 was associated with decreased risk of laryngeal cancer, with an OR of 0.70 (95% CI = 0.50–0.98) for carriers of the minor allele. Conclusions To our knowledge, this is the first report on the role of these polymorphisms with respect to UADT carcinogenesis. Our results suggest that inflammation-related polymorphisms play a role, albeit minor, in the risk of developing cancers of the upper aerodigestive tract.     

Green tea drinking,high tea temperature and esophageal cancer in high‐ and low‐risk areas of Jiangsu Province,China: A population‐based case–control study

Epidemiological studies suggested drinking green tea is inversely associated with esophageal cancer but results remain inconclusive. Moreover, inconsistent observations found high temperature drinks are associated with esophageal cancer. A population‐based case–control study was conducted in a high‐risk area (Dafeng) and a low‐risk area (Ganyu) of esophageal cancer in Jiangsu province China from 2003 to 2007. It aimed to explore green tea drinking and tea temperature with the risk of esophageal cancer, and to compare the difference between different risk regions. Using identical protocols, 1,520 cases and 3,879 healthy controls were recruited as study subjects in 2 regions. Detailed information was collected to assess green tea drinking habits. Unconditional logistic regression was used to obtain OR and 95% CI. Results showed that ever drinking green tea elevated OR in both counties (Dafeng OR = 1.2, 95% CI = 0.9–1.5; Ganyu: OR = 1.9, 95% CI = 1.4–2.4). Drinking tea at high temperature was found to increase cancer risk in both areas (Dafeng: OR = 1.9, 95% CI = 1.2–2.9; Ganyu OR = 3.1 95% CI = 2.2–4.3). However, after further adjustment for tea temperature, ever drinking tea was not related to cancer in either county (Dafeng: OR = 1.0, 95% CI = 0.7–1.3; Ganyu: OR = 1.3, 95% CI = 0.9–1.7). For dose‐response relationships, we observed positive relationship with monthly consumption of tea (p for trend = 0.067) and tea concentration (p for trend = 0.006) after further adjustment for tea temperature. In conclusion, green tea drinking was not inversely associated with esophageal cancer in this study. However, drinking tea at high temperatures significantly increased esophageal cancer risk. There was no obvious difference of green tea drinking between low‐ and high‐risk areas. © 2008 Wiley‐Liss, Inc.     

Associations of Lys939Gln and Ala499Val polymorphisms of the XPC gene with cancer susceptibility: A meta‐analysis

XPC polymorphisms may alter DNA repair capacity, thus leading to genetic instability and carcinogenesis. Numerous studies have investigated the associations of XPC Lys939Gln (rs2228001) and Ala499Val (rs2228000) polymorphisms with cancer susceptibility; however, the findings are inconclusive. We searched literature from MEDLINE and EMBASE for eligible publications that assessed the associations between these two polymorphisms and cancer risk. We also assessed genotype‐mRNA expression correlation data from HapMap for rs2228001 and rs2228000 in normal cell lines derived from 270 subjects with different ethnicities. The final analysis included 62 published studies of 25,708 cases and 30,432 controls for the Lys939Gln and 34 studies with 14,877 cases and 17,888 controls for the Ala499Val. Overall, Lys939Gln was significantly associated with an increased overall cancer risk (Gln/Gln vs. Lys/Lys: OR = 1.16, 95% CI = 1.07 − 1.25, p < 0.001; recessive model: OR = 1.14, 95% CI = 1.06 − 1.22, p < 0.001; dominant model: OR = 1.06, 95% CI = 1.01 − 1.11, p = 0.015 and Gln vs. Lys: OR = 1.07, 95% CI = 1.03 − 1.10, p < 0.001) and further stratifications showed an increased risk for bladder, lung and colorectal cancer, Asian populations and population‐based studies. Likewise, Ala499Val was also significantly associated with an increased overall cancer risk (Val/Val vs. Ala/Ala: OR = 1.21, 95% CI = 1.07 − 1.36, p = 0.003 and recessive model: OR = 1.20, 95% CI = 1.08 − 1.34, p = 0.001) and further stratification showed an increased risk for breast and bladder cancer, particularly in Asian populations. Interestingly, significantly correlation between XPC genotypes and mRNA expression was found only for Asian populations as well. Despite some limitations, this meta‐analysis established some solid statistical evidence for an association between XPC polymorphisms and cancer risk, which warrants further validation in single large studies.     

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Menopausal estrogen‐alone therapy (ET) is a well‐established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome‐wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case–control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non‐users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (p_int = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19–1.91), which was stronger for long‐term ET users of 10+ years (OR = 1.85, 95% CI 1.28–2.66, p_int = 0.034). Non‐users showed essentially no association (OR = 1.08, 95% CI 0.96–1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (p_int = 0.021 and p_int = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow‐up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.     

TP53 Arg72Pro polymorphism and lung cancer risk: A meta‐analysis

No clear consensus has been reached on the TP53 Arg72Pro polymorphism (G12139C) and lung cancer risk. Thus, a meta‐analysis was conducted to summarize the possible association. There was no statistical association between 12139C (Pro allele) and lung cancer risk in Caucasians compared with 12139G allele. However, the association was observed in all subjects (9,387 patients and 9,922 controls, p = 0.04, OR = 1.08, 95% CI 1.00–1.17), as well as in Asians (p = 0.0004, OR = 1.14, 95% CI 1.06–1.22). The association was also found in Asians under recessive genetic model (p < 0.00001, OR = 1.37, 95% CI 1.20–1.57) and homozygote comparison (CC vs. GG) (p < 0.0001, OR = 1.34, 95% CI 1.16–1.56). 12139C allele might increase the lung adenocarcinoma risk compared with 12139G allele (p = 0.01, OR = 1.11, 95% CI 1.02–1.21), and the effect was also found under recessive genetic model (p = 0.003, OR = 1.28, 95% CI 1.09–1.50) and homozygote comparison (CC vs. GG) (p = 0.007, OR = 1.28, 95% CI 1.07–1.52). There was an elevated association between the 12139C and the stage I lung cancer under dominant genetic model (p = 0.04, OR = 1.48, 95% CI 1.02–2.16), but no association was observed in other stages. No association of smoking was found between 12139C allele and lung cancer under recessive genetic model. Our result indicated that 12139C might increase the risk of lung cancer under recessive genetic model in adenocarcinoma, in Asians, and in lung cancer stage I. More studies stratified for lung cancer stage‐genotyping interaction should be performed to clarify the role of TP53 Arg72Pro polymorphism in the development of lung cancer. © 2009 UICC     

Genetic variants in pigmentation genes,pigmentary phenotypes,and risk of skin cancer in Caucasians

Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. We evaluated the associations between 15 SNPs in 8 candidate pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP and ATRN) and both pigmentary phenotypes (hair color, skin color and tanning ability) and skin cancer risk in a nested case‐control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases and 870 common controls. We found that the TYR Arg402Gln variant was significantly associated with skin color (p‐value = 7.7 × 10^?4) and tanning ability (p‐value = 7.3 × 10^?4); the SLC45A2 Phe374Leu variant was significantly associated with hair color (black to blonde) (p‐value = 2.4 × 10^?7), skin color (p‐value = 1.1 × 10^?7) and tanning ability (p‐value = 2.5 × 10^?4). These associations remained significant after controlling for MC1R variants. No significant associations were found between these polymorphisms and the risk of skin cancer. We observed that the TYRP1 rs1408799 and SLC45A2 1721 C>G were associated with melanoma risk (OR, 0.77; 95% CI, 0.60–0.98 and OR, 0.75; 95% CI, 0.60–0.95, respectively). The TYR Ser192Tyr was associated with SCC risk (OR, 1.23; 95% CI, 1.00–1.50). The TYR haplotype carrying only the Arg402Gln variant allele was significantly associated with SCC risk (OR, 1.35; 95% CI, 1.04–1.74). The OCA2 Arg419Gln and ASIP g.8818 A>G were associated with BCC risk (OR, 1.50; 95% CI, 1.06–2.13 and OR, 0.73; 95% CI, 0.53–1.00, respectively). The haplotype near ASIP (rs4911414[T] and rs1015362[G]) was significantly associated with fair skin color (OR, 2.28; 95% CI, 1.46–3.57) as well as the risks of melanoma (OR, 1.68; 95% CI, 1.18–2.39) and SCC (OR, 1.54; 95% CI, 1.08–2.19). These associations remained similar after adjusting for pigmentary phenotypes and MC1R variants. The statistical power of our study was modest and additional studies are warranted to confirm the associations observed in the present study. Our study provides evidence for the contribution of pigmentation genetic variants, in addition to the MC1R variants, to variation in human pigmentary phenotypes and possibly the development of skin cancer. © 2009 UICC