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.     

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.     

Blood leukocyte DNA hypomethylation and gastric cancer risk in a high‐risk Polish population

Global hypomethylation has been shown to increase genome instability potentially leading to increased cancer risk. We determined whether global methylation in blood leukocyte DNA was associated with gastric cancer in a population‐based study on 302 gastric cancer cases and 421 age‐ and sex‐matched controls in Warsaw, Poland, between 1994 and 1996. Using PCR‐pyrosequencing, we analyzed methylation levels of Alu and LINE‐1, 2 CG‐rich repetitive elements, to measure global methylation levels. Gastric cancer risk was highest among those with lowest level of methylation in either Alu (OR = 1.3, 95% CI = 0.9–1.9) or LINE‐1 (OR = 1.4, 95% CI = 0.9–2.0) relative to those with the highest levels, although the trends were not statistically significant. For Alu, the association was stronger among those aged 70 or older (OR = 2.6, 95% CI = 1.3–5.5, p for interaction = 0.02). We did not observe meaningful differences in the associations by other risk factors and polymorphisms examined. For LINE‐1, the association tended to be stronger among individuals with a family history of cancer (OR = 3.1, 95% CI = 1.4–7.0, p for interaction = 0.01), current alcohol drinkers (OR = 1.9, 95% CI = 1.0–3.6, p for interaction = 0.05), current smokers (OR = 2.3, 95% CI = 1.1–4.6, p for interaction = 0.02), those who rarely or never consumed fruit (OR = 3.1, 95% CI = 1.2–8.1, p for interaction = 0.03), CC carriers for the MTRR Ex5+123C>T polymorphism (OR = 2.3, 95% CI = 1.2–4.4, p for interaction = 0.01) and TT carriers for the MTRR Ex15+572T>C polymorphism (OR = 1.7, 95% CI = 1.0–2.8, p for interaction = 0.06). The association was not different by sex, Helicobacter pylori infection, intake of folate, vitamin B6 and total protein and the remaining polymorphisms examined. Our results indicate that interactions between blood leukocyte DNA hypomethylation and host characteristics may determine gastric cancer risk.     

Fine–mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans,Melanesians and Polynesians

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality.At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10^-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10^-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue.Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.     

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.     

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.     

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.     

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.     

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     

Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a chinese population

Genetic factors play important roles in pathogenesis of human cancer. A recent genome‐wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate stem cell antigen (PSCA), rs2294008C>T and rs2976392G>A, to risk of diffuse‐type of gastric cancer in Japanese and Korean populations. We hypothesized that these two SNPs are also associated with risk of gastric cancer in Chinese population. We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13–1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01–1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to developing poorly differentiated and high stage NCGC at diagnosis. However, no such association was detected for CGC. In addition, we observed considerably lower allelic and genotype frequencies of these genetic variants in Chinese population compared with Japanese and Korean populations. These findings are in general consistent with previous GWAS and suggest that PSCA may play a role in the development of NCGC in Chinese population. © 2009 Wiley‐Liss, Inc.     

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.     

Family history of cancer and risk of sporadic differentiated thyroid carcinoma

BACKGROUND:

Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since the 1980s. Although the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid carcinoma (DTC). Therefore, the authors explored the association between sporadic DTC and family history of cancer.

METHODS:

In a retrospective hospital‐based case‐control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first‐degree family history of cancer.

RESULTS:

The study included 288 patients with sporadic DTC and 591 cancer‐free controls. Family history of thyroid cancer in first‐degree relatives was associated with increased DTC risk (adjusted OR, 4.1; 95% CI, 1.7‐9.9). All DTC cases in patients with a first‐degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR, 4.6; 95% CI, 1.9‐11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR, 7.4; 95% CI, 1.8‐30.4). In addition, multifocal primary tumor was more common among PTC patients with first‐degree family history of thyroid cancer than among PTC patients with no first‐degree family history of thyroid cancer (68.8% vs 35.5%, P = .01).

CONCLUSIONS:

The study suggests that family history of thyroid cancer in first‐degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC. Cancer 2012;. © 2011 American Cancer Society.     

Dietary carotenoids and the risk of invasive breast cancer

Certain classes of vitamins and nutrients found in fruits and vegetables have been of particular interest in relation to cancer prevention, owing to their potential anticarcinogenic properties. We examined the association between certain fruits, vegetables, carotenoids, and vitamin A and breast cancer risk in a large population‐based case‐control study of women residing in the states of Massachusetts, New Hampshire and Wisconsin. The study was comprised of 5,707 women with incident invasive breast cancer (2,363 premenopausal women and 3,516 postmenopausal women) and 6,389 population controls (2,594 premenopausal women and 3,516 postmenopausal women). In an interview, women were asked about their intake of carotenoid rich fruits and vegetables 5 years prior to a referent date. An inverse association observed among premenopausal women was for high levels of vitamin A (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.01), β‐carotene (OR: 0.81, 95% CI 0.68–0.98, p for trend = 0.009), α‐carotene (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.07) and lutein/zeaxanthin (OR: 0.83, 95% CI 0.68–0.99, p for trend = 0.02). An inverse association was not observed among postmenopausal women. Among premenopausal women who reported ever smoking, these results were stronger than among never smokers, although tests for interaction were not statistically significant. Results from this study are comparable to previous prospective studies, and suggest that a high consumption of carotenoids may reduce the risk of premenopausal but not postmenopausal breast cancer, particularly among smokers. © 2009 UICC     

Serum 25(OH)D concentration,common variants of the VDR gene and lung cancer occurrence

The first aim of our study was to examine the association between common variants in VDR [rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI) and rs11568820 (Cdx2)] and lung cancer risk in the Polish population. Genotyping and statistical analysis which included Chi‐square test with Yates correction and haplotype frequency analysis were performed on a series of 840 consecutively collected lung cancer patients and 920 healthy controls. The second aim was to evaluate the link between serum 25(OH)D concentration and the number of lung cancers in a subgroup of 200 patients. A separate control group that consisted of 400 matched (by age, sex, smoking habits and the season of blood collection) healthy individuals was used to avoid posterior adjustment on the matched variables. Statistical analysis with the use of Chi‐square test with Yates was performed. We found no statistically significant difference in the distribution of the allels of studied VDR variants among cases and controls. A statistically significant over‐representation of VDR haplotypes: rs731236_A + rs1544410_T [odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.11–5.32, p < 0.001], rs731236_G + rs1544410_T (OR = 1.54, 95% CI = 1.31–1.81, p < 0.001) and rs731236_G + rs1544410_C (OR = 0.04, 95% CI = 0.03–0.07, p < 0.001) was detected. We found a tendency toward an increased number of lung cancers among individuals with low serum levels of 25(OH)D. To answer the question, whether VDR can be regarded as lung cancer susceptibility gene and low 25(OH)D serum levels is associated with lung cancer occurrences, additional, multicenter study needs to be performed.     

Genetic variation of PSCA gene is associated with the risk of both diffuse‐ and intestinal‐type gastric cancer in a Chinese population

Prostate stem cell antigen (PSCA), a member of the LY‐6/Thy‐1 family of glycosylphosphatidylinositol‐anchored cell surface proteins, is considered to be involved in the cell‐proliferation inhibition and/or cell‐death induction activity. Two single nucleotide polymorphisms (SNPs) (rs2976392 and rs2294008) in the PSCA gene were recently identified as the susceptibility loci of gastric cancer, especially in diffuse type. Therefore, this study was to investigate whether these 2 SNPs were associated with the risk of gastric cancer in Chinese population. We genotyped rs2976392 and rs2294008 in PSCA in a case–control study including 1,053 incident gastric cancer patients and 1,100 cancer‐free controls in a high‐risk Chinese population. We found that variant genotypes of rs2976392 (GA/AA) were associated with a significantly 37% increased risk of gastric cancer (adjusted OR =1.37, 95% CI = 1.15–1.62), compared with variant homozygote GG, and the associations were all consistently significant in both intestinal and diffuse subtypes, and among different subgroups stratified by age, sex, drinking or smoking status. Interestingly, a significant multiplicative interaction between rs2976392 (GA/AA) and alcohol drinking was detected on the development of intestinal‐type gastric cancer (p = 0.009). However, rs2294008 variant genotypes (CT/TT) were associated with a nonsignificant increased risk of gastric cancer (adjusted OR = 1.14, 95% CI = 0.96–1.36). A small meta‐analysis including 5 case–control studies showed undoubtedly associations between PSCA rs2294008 and rs2976392 and gastric cancer risk (OR = 1.83, 95% CI: 1.29–2.60 and OR = 1.84, 95% CI: 1.33–2.56, respectively). These findings provide further evidence supporting that the genetic variants of PSCA gene may contribute to the gastric carcinogenesis.     

Melanocortin receptor 1 variants and melanoma risk: A study of 2 European populations

Variation within the melanocortin receptor 1 (MC1R) gene, that influences phenotypic traits and susceptibility to melanoma, is abundant across the populations. We assessed and compared the risk of melanoma in 2 European populations, German and Spanish, by genotyping MC1R variants through direct DNA sequencing from 1,185 melanoma cases and 1,582 controls. The presence of any variant in both populations was associated with a significantly increased risk of melanoma (odds ratio OR = 1.67, 95% confidence interval CI 1.40–1.99). The population attributable fractions (PAF) associated with the MC1R variants in both populations was over 25%. However, the results showed a statistically significant (p < 0.0001) higher frequency of MC1R variants in the German (70%) than in the Spanish population (60%). The red‐hair colour (RHC) variants, though associated with increased risk in both populations, were more common in the German than in the Spanish population (p < 0.0001). Interestingly, non‐RHC variants increased the disease risk in the Spanish (OR = 1.60, 95% CI 1.20–2.14) but not in the German population (OR = 1.07, 95% CI 0.80–1.44). Although RHC variants explained a major proportion of the observed PAF in the German population, in the Spanish population the major contributor to the PAF was the non‐RHC V60L variant. We also observed reduced historic linkage disequilibrium between the variants V92M and T314T in the gene in German melanoma cases. In conclusion, our data underscored the unambiguous importance of the MC1R variants towards the population burden of melanoma. However, the variants that are associated with the disease differ between the investigated populations. © 2009 UICC     

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.     

Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations

Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome‐wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well‐defined Southern European case‐control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10^?22, rs7037324: OR = 1.54, p = 1.2 × 10^?17). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10^?04, OR = 1.26, p = 5.2 × 10^?04 and OR = 1.38, p = 5.9 × 10^?05, respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10^?04). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease.     

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.     

Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Genome‐wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome‐wide association study in 1,701 CRC cases and 14,082 cancer‐free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single‐nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10⁻⁴; OR, 1.14; 95% CI, 1.06–1.23), and it was genome‐wide significant in combined analysis (p = 1.50 × 10⁻⁹; OR, 1.12; 95% CI, 1.08–1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.