Host genetic susceptibility has been suggested as one of the most important possible explanations for interindividual difference in gastric cancer (GC) risk.

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor alpha (ERalpha) pathway. Among these it was shown that GATA3 associates with the promoter of the ERalpha gene and ERalpha can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERalpha to determine the depth of overlap.

A number of protein markers have been investigated as prognostic adjuncts in breast cancer but their translation into clinical practice has been impeded by a lack of appropriate validation. Recently, we showed that BCL2 protein expression had prognostic power independent of current used standards. Here, we present the results of a meta-analysis of the association between BCL2 expression and both disease free survival (DFS) and overall survival (OS) in female breast cancer.

The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a meta-analysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/index.html ). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The meta-analysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-ORm2/m2: 1.9, 95% confidence interval: 1.4-2.7; Pooled ORm2m2: 2.0, 95% confidence interval: 1.3-3.1; ORm1m2 or [infi]m2m2: 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (ORVal/Val: 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer.

During the last several decades, numerous researchers have examined the potential of in vitro and /or in vivo exposure of radiofrequency( RF) radiation to damage the genetic material in mammalian somatic cells. A meta-analysis of reported data was conducted to obtain a quantitative estimate ( with 95% confidence intervals) of genotoxicity in RF-radiation-exposed cells compared with sham-exposed/unexposed control cells. The extent of genotoxicity was assessed for various end points, including single- and double-strand breaks in the DNA, incidence of chromosomal aberrations, micronuclei and sister chromatid exchanges. Among the several variables in the experimental protocols used in individual investigations, the influence of three specific variables related to RF-radiation exposure characteristics was examined in the meta-analysis: frequency, specific absorption rate, and exposure as continuous-wave, pulsed-wave and occupationally exposed/cell phone users. The overall data indicated that (1) the difference between RF-radiation exposure was small with few exceptions; (2) at certain RF radiation exposure conditions, there were statistically significant increases in genotoxicity for some end points; and (3) the mean indices for chromosomal aberrations and micronuclei in RF-radiation -exposed and sham-/unexposed controls were within the spontaneous levels reported in the historical database. Considerable evidence for publication bias was found in the meta-analysis.

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. Several polymorphisms in the XRCC1 gene have been described, including Arg399Gln. Previous studies investigating the association between genetic polymorphism of Arg399Gln XRCC1 and risk of breast cancer have provided inconsistent results. A meta-analysis was conducted to investigate the association between common genetic variant in the XRCC1 gene (exon 10, Arg399Gln) with breast cancer risk. We identified 36 eligible studies, in relation to the Arg399Gln polymorphism of XRCC1 and risk of breast cancer. These studies comprised of 43,716 subjects (20,837 patients and 22,879 controls). We first estimated the risk of the genotypes Arg/Gln and Gln/Gln compared with the wild-type Arg/Arg homozygote, and then evaluated the risk of Gln/Gln versus (Arg/Gln+Arg/Arg) and (Gln/Gln+Arg/Gln) versus Arg/Arg, which assumed recessive and dominant effects, respectively, of the variant 399Gln allele. There was significant heterogeneity between studies. The overall ORs showed that the breast cancer risk were not associated with the XRCC1 genotypes. The heterogeneity between studies decreased dramatically when studies stratified into Asian and Western countries. There was significant association between the polymorphism of XRCC1 and breast cancer risk among studies of Asian countries. In Asian countries the Arg/Gln versus Arg/Arg (OR = 0.98, 95% CI: 0.88-1.10) and Gln/Gln+Arg/Gln versus Arg/Arg (OR = 1.05, 95% CI: 0.95-1.18) were not associated with increased risk of breast cancer. On the other hand, both Gln/Gln versus Arg/Arg (OR = 1.46, 95% CI: 1.19-1.79) and Gln/Gln versus Arg/Gln+Arg/Arg (OR = 1.49, 95% CI: 1.22-1.81) increased the risk. Therefore, it could be concluded that 399Gln allele might act as a recessive allele in its association with breast cancer risk.

The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone. A non-synonymous single-nucleotide polymorphism, A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999, we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype [odds ratio (OR) = 1.16, 95% confidence interval (CI) 0.79-1.69] in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men, respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating more than 6000 cases and 6000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.

A sensitive and acceptable screening regimen for women at high risk for breast cancer is essential. Contrast-enhanced magnetic resonance imaging (MRI) of the breast is highly sensitive for diagnosis of breast cancer but has variable specificity.

To evaluate the association between HER2 codon 655 polymorphism and breast cancer risk in this meta-analysis. A comprehensive search was performed to identify all case-control studies investigating such association. Statistical analyses were conducted with software MIX 1.54. Twenty eligible reports, including 10,642 cases/11,259 controls, were identified. In overall analysis, the Val allele frequency in cases was significantly higher than that in controls (OR = 1.0921, 95% CI: 1.0013-1.191, P = 0.0466), while no associations were found in both recessive and dominant models. In subgroup analysis, HER2 codon 655 polymorphism was weakly associated with breast cancer risk in recessive (OR = 2.4624, 95% CI: 1.0619-5.7104, P = 0.0357), dominant (OR = 1.2781, 95% CI: 1.0353-1.5779, P = 0.0225), and co-dominant genetic models (OR = 1.2947, 95% CI: 1.0682-1.5693, P = 0.0085) in Asian population, respectively. Meanwhile, the susceptibility to breast cancer in people aged < or =45 was significantly increased in both recessive (OR = 2.2408; 95% CI: 1.2876-3.8998, P = 0.0043), and dominant models (OR = 1.2902, 95% CI: 1.1035-1.5085, P = 0.0014). No significant associations were observed in Caucasian, European, and Family history subgroups. So our analyses suggest HER2 codon 655 Val allele is weakly associated with an increased risk of breast cancer, and SNP at HER2 codon 655 could be considered as a susceptibility biomarker for breast cancer for Asian females or women age 45 years or younger.

The aim of this report is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of head and neck cancer (HNC). All relevant studies available in MEDLINE and published before July 2007 were identified. Studies carried out in humans that compared HNC patients with at least 1 standard control group were considered for analysis. Two hundred and eighteen publications and 3 published meta-analyses were identified. Seventy-five (34%) studies were conducted in Asian, 72 (33%) in American, and 68 (31%) in European countries. The most widely studied gene was GSTM1 (58 studies), followed by GSTT1 (42 studies), GSTP1 (codon 105, 22 studies) and p53 (codon 72, 20 studies). GSTM1, GSTT1, GSTP1, XRCC1 codons 194 and 399, and CYP1A1 codon 462 were examined by meta-analyses, and significant relations were found between the GSTM1-null genotype and an increased risk for HNC. In addition, increased risk for HNC was associated consistently with the ALDH2*1/*2, p53 codon 72 Pro/Pro and EPHX1 codon 113 Tyr/His and His/His genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in carcinogenesis of the head and neck are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions.

Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less common cancers require accurate, age-specific risk estimation. We pooled data from 4 LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6,041 members of 261 families with LS-associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N = 98) had an overall lifetime risk (to age 70) of 8.4% (95% CI: 6.6-10.8); risks were higher in males (p < 0.02) and members of MSH2 families (p < 0.0001). Ovarian cancer (N = 72) had an lifetime risk of 6.7% (95% CI: 5.3-9.1); risks were higher in women born after the median year of birth (p < 0.008) and in members of MSH2 families (p < 0.006). Brain tumors and cancers of the small bowel, stomach, breast and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions.

Melanocortin-1-receptor (MC1R) is one of the major genes that determine skin pigmentation. MC1R variants were suggested to be associated with red hair, fair skin, and an increased risk of melanoma. We performed a meta-analysis on the association between the 9 most studied MC1R variants (p.V60L, p.D84E, p.V92M, p.R142H, p.R151C, p.I155T, p.R160W, p.R163Q and p.D294H) and melanoma and/or red hair, fair skin phenotype. Eleven studies on MC1R and melanoma, and 9 on MC1R and phenotype were included in the analysis. The 7 variants p.D84E, p.R142H, p.R151C, p.I155T, p.R160W, p. R163Q and p.D294H were significantly associated with melanoma development, with ORs (95%CI) ranging from 1.42 (1.09-1.85) for p.R163Q to 2.45 (1.32-4.55) for p.I155T. The MC1R variants p.R160W and p.D294H were associated both with red hair and fair skin, while p.D84E, p.R142H, and p.R151C were strongly associated with red hair only- ORs (95%CI) ranged from 2.99 (1.51-5.91) for p.D84E to 8.10 (5.82-11.28) for p.R151C. No association with melanoma or phenotype was found for p.V60L and p.V92M variants. In conclusion this meta-analysis provided evidence that some MC1R variants are associated both with melanoma and phenotype, while other are only associated with melanoma development. These results suggest that MC1R variants could play a role in melanoma development both via pigmentary and non-pigmentary pathways.

Several studies have suggested that microsatellite instability (MSI) resulting from defective DNA mismatch repair confers a better prognosis in colorectal cancer (CRC). Recently, however, data have suggested this is secondary to the effects of ploidy/chromosomal instability (CIN). To estimate the prognostic significance of CIN for survival, data from published studies have been reviewed and pooled.

We conducted a meta-analysis to assess the association between tumor necrosis factor-alpha (TNF-alpha) gene TNFA-308 (G > A) and TNFA-857 (C > T) polymorphisms and gastric cancer (GC) susceptibility. We also performed subgroup analyses based on ethnicity (Caucasian, east Asian, and other populations) and tumor location [noncardia gastric cancer (NCGC)]. There were 3,335 GC patients and 5,286 controls for TNFA-308, and 1,118 GC patients and 1,591 controls for TNFA-857 in our analysis. Overall, allele contrast (A vs. G) of TNFA-308 polymorphism produced significant results in worldwide populations [Pheterogeneity = 0.05, random-effects (RE) odds ratio (OR) 1.19; 95% confidence interval (CI) 1.03-1.37, P = 0.02] and Caucasian populations (Pheterogeneity = 0.15, fixed-effects (FE), OR 1.27; 95% CI 1.11-1.45, P = 0.0005). Similar results were also obtained in recessive models and homozygote contrasts. No significant association was observed in NCGC and east Asian subgroup analysis. T variant of TNFA-857 produced significant results only in allele contrast (Pheterogeneity = 0.38, FE OR 1.17; 95% CI 1.01-1.35, P = 0.04). In conclusion, TNFA-308 locus of TNF-alpha would be a risk factor for GC, especially in Caucasian populations. Besides, TNFA-857 locus may be related to GC risk, which demonstrated changeability of results in different contrasts.

Case-control studies investigating associations between multiple myeloma (MM) and the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) have provided controversial results. In an attempt to interpret these results, a meta-analysis of all available studies was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using fixed effects (FE) and random effects (RE) models. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. The meta-analysis revealed non-significant heterogeneity between studies (Pq > or = 0.65). The dominant model for the effect of 677T allele produced significant association overall [FE OR = 1.23 (1.04-1.47)] and in Caucasians [FE OR = 1.54 (1.14-2.08)], but not in East Asians [FE OR = 1.05 (0.82-1.34)]. Although the cumulative meta-analysis for the dominant model of 677T allele showed a downward trend of RE OR for the period 2000-2007, the association still remained significant. Analysis of the A1298C polymorphisms revealed lack of association both in Caucasians and in East Asians. There is an indication of potential bias: a differential magnitude of effect in large versus small studies emerged. In conclusion, the accumulated evidence indicated an association between MTHFR C677T polymorphism and MM in Caucasians under a dominant model.

Elucidation of candidate colorectal cancer biomarkers often begins by comparing the expression profiles of cancerous and normal tissue by performing gene expression profiling. Although many such studies have been done, the resulting lists of differentially expressed genes tend to be inconsistent with each other, suggesting that there are some false positives and false negatives. One solution is to take the intersection of the lists from independent studies. However, often times, the statistical significance of the observed intersection are not assessed.

Genetic variations in the XPD gene may increase cancer susceptibility by affecting the capacity for DNA repair. Several studies have investigated this possibility; however, the conclusions remain controversial. Therefore, we did a systematic review and executed a meta-analysis to explore the association. From 56 studies, a total of 61 comparisons included 25,932 cases and 27,733 controls concerning the Lys 751Gln polymorphism; 35 comparisons included 16,781 cases and 18,879 controls in the case of Asp 312 Asn were reviewed. In this analysis, small associations of the XPD Lys 751 Gln polymorphism with cancer risk for esophageal cancer [for Lys/Gln versus Lys/Lys: odds ratio (OR), 1.34; 95% confidence interval (95% CI), 1.10-1.64; for Gln/Gln versus Lys/Lys: OR, 1.61; 95% CI, 1.16-2.25] and acute lymphoblastic leukemia (for Gln/Gln versus Lys/Lys: OR, 1.83; 95% CI, 1.21-2.75) are revealed. Overall, individuals with the Gln/Gln genotype have a small cancer risk compared with Lys/Lys genotype for the reviewed cancer in total (OR, 1.10; 95% CI, 1.03-1.16). Subtle but significant cancer risk was observed for the XPD Asp 312 Asn polymorphism in bladder cancer (for Asp/Asn versus Asp/Asp: OR, 1.24; 95% CI, 1.06-1.46). No significant associations were found for other cancers separately and all the reviewed cancer in total assessed for the Asp 312 Asn polymorphism. Our study suggests that XPD is a candidate gene for cancer susceptibility regardless of environmental factors.

Bulky DNA adducts are biomarkers of exposure to aromatic compounds and of the ability of the individual to metabolically activate carcinogens and to repair DNA damage. Their ability to predict cancer onset is uncertain. We have performed a pooled analysis of three prospective studies on cancer risk in which bulky DNA adducts have been measured in blood samples collected from healthy subjects (N = 1947; average follow-up 51-137 months). In addition, we have performed a meta-analysis by identifying all articles on the same subject published up to the end of 2006, including case-control studies. In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls). The association was evident only in current smokers and was absent in former smokers. Also the meta-analysis, which included both lung and bladder cancers, showed a statistically significant association in current smokers, whereas the results in never smokers were equivocal; in former smokers, no association was detected. The results of our pooled and meta-analyses suggest that bulky DNA adducts are associated with lung cancer arising in current smokers after a follow-up of several years.

So far, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and lung cancer provide controversial or inconclusive results. To clarify the effect of MTHFR polymorphisms on the risk of lung cancer, a meta-analysis of all case-control observational studies was performed. The studies provided 5,111/6,415 cases/controls for C677T and 5,087/6,232 cases/controls for A1298C. The heterogeneity (P=0.0001, I(2)=76.6%) for C677T among the eight studies was extreme. Cluster analyses based on the frequencies of the C677T genotype of the control group in each study revealed that the studies could not cluster together according to their ethnicity. The random effects (RE) model showed that the 677T allele was not associated with the risk of lung cancer compared with the C allele [OR=1.12, 95% confidence interval (CI) (0.97-1.28), P=0.12]. The contrast of homozygotes, recessive model, dominant model produced the same pattern of results as the allele contrast. In regard to the A1298C polymorphism, there was no heterogeneity among the seven studies comparing the C versus the A allele (P=0.24, I(2)=24.4%), but no significant association was detected by the RE model or the fixed effects model [FE odds ratio (OR)=0.99 (0.93-1.05) and RE OR=1.00 (0.92-1.08)]. The effect of MTHFR polymorphisms (C677T, A1298C) on the risk of lung cancer was undetectable, even though analyzed on a relatively good number of subjects (totally 11,526 subjects) by meta-analysis (statistical power = 93.9%). Although MTHFR polymorphisms were associated with the risk of colorectal cancer, leukemia, and gastric cancer supported by other meta-analysis, our pooled data suggest no evidence for a major role of these two variants in carcinogenesis of lung cancer. The results implied that different tumors evolve by different pathological pathways and the roles of MTHFR in cancer is determined by its target genes.