Single-nucleotide polymorphisms in the RB1 gene and association with breast cancer in the British population

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. pRb controls the cell cycle and polymorphisms within it are candidates for such low penetrance susceptibility alleles, since the gene has been implicated in several human tumours, particularly breast cancer. The purpose of this study was to determine whether common variants in the RB1 gene are associated with breast cancer risk. We assessed 15 tagging single-nucleotide polymorphisms (SNPs) using a case-control study design (n< or = 4474 cases and n < or = 4560 controls). A difference in genotype frequencies was found between cases and controls for rs2854344 in intron 17 (P-trend = 0.007) and rs198580 in intron 19 (P-trend = 0.018). Carrying the minor allele of these SNPs appears to confer a protective effect on breast cancer risk (odd ratio (OR) = 0.86 (0.76-0.96) for rs2854344 and OR = 0.80 (0.66-0.96) for rs198580). However, after adjusting for multiple testing these associations were borderline with an adjusted P-trend = 0.068 for the most significant SNP (rs2854344). The RB1 gene is not known to contain any coding SNPs with allele frequencies > or = 5% but several intronic variants are in perfect linkage disequilibrium with the associated SNPs. Replication studies are needed to confirm the associations with breast cancer.     

Consortium analysis of 7 candidate SNPs for ovarian cancer

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.     

Common variants in mismatch repair genes and risk of invasive ovarian cancer

Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P(2df) = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P(7df) = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs--MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)--but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.     

Genetic polymorphisms in the Paraoxonase 1 gene and risk of ovarian epithelial carcinoma

Oxidative stress during successive ovulations increases the opportunity for DNA damage to ovarian epithelial cells and the potential for malignant transformation. Paraoxonase 1 (PON1) is an endogenous free radical scavenger that reduces oxidative stress. The association of two common functional single nucleotide polymorphisms (SNP), rs854560 T>A and rs662 A>G, with the risk of epithelial ovarian cancer was examined in a population-based case-control study in Hawaii. A personal interview and blood specimens were collected from 274 women with histologically confirmed, primary ovarian cancer and 452 controls frequency matched on age and ethnicity. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Both PON1 SNPs were significantly associated with ovarian cancer risk. The ORs were 0.53 (95% CI, 0.35-0.79; P for allele-dose effect = 0.01) for women carrying the rs854560 T allele compared with women with the AA genotype and 0.65 (95% CI, 0.44-0.95; P for allele-dose effect = 0.03) for women carrying the rs662 A allele compared with women with the GG genotype. The association of the rs854560 T genotype with risk was stronger among smokers (OR, 0.33; 95% CI, 0.17-0.64; P for allele-dose effect = 0.0007) than among nonsmokers (OR, 0.68; 95% CI, 0.40-1.18; P for allele-dose effect = 0.53). The decreased risk associated with the rs854560 T allele was also stronger among obese women (OR, 0.19; 95% CI, 0.06-0.55; P for allele-dose effect = 0.007) than among nonobese women (OR, 0.62; 95% CI, 0.40-0.98; P for allele-dose effect = 0.16). Our study provides evidence for an association of two PON1 SNPs with the risk of epithelial ovarian cancer. Possible effect modification of these associations by tobacco smoking and obesity needs confirmation in other studies.     

Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer

Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.     

Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach.

Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging approach to search for low-penetrance susceptibility alleles in a study of up to 4,647 cases and 4,564 controls, in a two-stage study design. We identified seven tagging SNPs using genotype data from the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project and typed these, and an additional three SNPs, in 2,345 breast cancer cases and 2,284 controls (set 1). Three SNPs showed no evidence for association and were not studied further, whereas seven SNPs (rs11571171, rs7116336, rs660149, rs10895068, rs500760, rs566351, and rs1042838) exhibited significant associations at P < 0.1 using either a heterogeneity or trend test and progressed to be genotyped in set 2. After both stages, only one SNP was significantly associated with an increased risk of breast cancer - the PGR-12 (rs1042638) V660L valine to leucine polymorphism [VL heterozygotes (odds ratio, 1.13; 95% confidence interval, 1.03-1.24) and the LL homozygotes (odds ratio, 1.30; 95% confidence interval, 0.98-1.73), P(het) = 0.008, P(trend) = 0.002]. Similar estimates were obtained in a combined analysis of our data with those from three other published studies. We conclude that the 660L allele may be associated with a moderately increased risk of breast cancer, but that other common SNPs in the PGR gene are unlikely to be associated with a substantial risk of breast cancer.     

Ovarian cancer risk associated with inherited inflammation-related variants

The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P(heterogeneity) = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.     

Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: results from two Australian studies and an additional validation set.

Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r(2) = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition.     

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.     

Genetic variation in the one-carbon transfer pathway and ovarian cancer risk

Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A>G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0-1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3' untranslated region (UTR) C>G (rs13420827: OR, 0.8; 95% CI, 0.6-1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G>A (rs11887120: OR, 0.8; 95% CI, 0.7-1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A>T (rs11695471: OR, 1.2; 95% CI, 1.0-1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk.     

Comprehensive evaluation of ESR2 variation and ovarian cancer risk.

Studies indicate that estrogen receptor beta, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of > or =5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum R(h)(2) of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk.     

A genome-wide association study identifies a locus on chromosome 14q21 as a predictor of leukocyte telomere length and as a marker of susceptibility for bladder cancer

Telomeres play a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many aging-related diseases. Classic twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. In the study we report here that we used a multistage genome-wide association study to identify genetic determinants of telomere length. The mean telomere length in peripheral blood leukocytes was measured by quantitative real-time PCR. We first analyzed 300,000 single-nucleotide polymorphisms (SNPs) in 459 healthy controls, finding 15,120 SNPs associated with telomere length at P < 0.05. We then validated these SNPs in two independent populations comprising 890 and 270 healthy controls, respectively. Four SNPs, including rs398652 on 14q21, were associated with telomere length across all three populations (pooled P values of <10(-5)). The variant alleles of these SNPs were associated with longer telomere length. We then analyzed the association of these SNPs with the risk of bladder cancer in a large case-control study. The variant allele of rs398652 was associated with a significantly reduced risk of bladder cancer (odds ratio = 0.81; 95% confidence interval, 0.67-0.97; P = 0.025), consistent with the correlation of this variant allele with longer telomeres. We then conducted a mediation analysis to examine whether the association between rs398652 and reduced bladder cancer risk is mediated by telomere length, finding that telomere length was a significant mediator of the relationship between rs398652 and bladder cancer (P = 0.013), explaining 14% of the effect. In conclusion, we found that the SNP rs398652 on 14q21 was associated with longer telomere length and a reduced risk of bladder cancer and that a portion of the effect of this SNP on bladder cancer risk was mediated by telomere length.     

Sequence variants of elaC homolog 2 (Escherichia coli) (ELAC2) gene and susceptibility to prostate cancer in the Health Professionals Follow-Up Study

Two non-synonymous single-nucleotide polymorphisms (SNPs), Ser217Leu and Ala541Thr, in the elaC homolog 2 (Escherichia coli) (ELAC2) gene have been related to prostate cancer risk in previous studies, though with inconsistent results. The association of ELAC2 haplotypes with prostate cancer risk has not yet been explored. We assessed whether sequence variants in ELAC2 were associated with the risk of total or aggressive prostate cancer. In a nested case-control design within the Health Professionals Follow-Up Study, we identified 659 participants with prostate cancer diagnosed after they provided a blood specimen in 1993 and before January 2000. Controls were 656 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped eight tagging SNPs in ELAC2 to test for the association between sequence variances in ELAC2 and prostate cancer. No individual SNP (including Ser217Leu) was associated with the risk of prostate cancer. Ala541Thr is a rare SNP in this population. One common haplotype (hap4) was statistically significantly associated with an increased risk of prostate cancer [odds ratio (OR) = 1.39, 95% confidence interval = 1.05-1.85]. Two common promoter SNPs and three common haplotypes were statistically significantly associated with aggressive prostate cancer (carriers versus non-carriers-snp2: OR = 1.43, snp3: OR = 0.69, hap1: OR = 1.47, hap2: OR = 0.72, hap4: OR = 1.51; global P-value for all common haplotypes = 0.11). Common SNPs and haplotypes of ELAC2 were associated with risk of aggressive prostate cancer.     

Association between single nucleotide polymorphisms on chromosome 17q and the risk of prostate cancer in a Chinese population

In European populations, 7 single nucleotide polymorphisms (SNPs) on chromosome 17q, 3 SNPs on 17q12, and 4 SNPs on 17q24.3 were recently identified to be closely related to the risk of prostate cancer by a genome-wide association study. In Japanese populations, the correlation between 2 SNPs on 17q and the risk of prostate cancer and tumor aggressiveness was also confirmed by a large-scale experiment. However, whether 17q is associated with prostate cancer and its clinical manifestations in Chinese populations is still unknown. Therefore, we conducted a case-control study in a northern Chinese population and tested 2 SNPs, rs4430796 and rs1859962, on 17q in 124 prostate cancer patients and 111 controls using polymerase chain reaction-high resolution melting curve (PCR-HRM) combined with sequencing. We analyzed the association of the 2 SNPs with the risk of prostate cancer as well as patients' lifestyles, onset ages, Gleason scores, PSA levels, and pathologic stages. We found a significant difference in the G allele of SNP rs1859962 (P = 0.035, OR = 1.51, 95% CI = 1.03-2.21) but not in the rs4430796 genotype frequency or allele frequency distribution between prostate cancer patients and the controls (P > 0.05). Neither of the SNPs was significantly associated with the onset age, Gleason score, PSA level, pathologic stage, or other clinical indicators of patients with prostate cancer (P > 0.05). Our results show that polymorphism of the G allele of SNP rs1859962 is associated with the risk of prostate cancer in a Chinese population.     

Polymorphic variants in PTGS2 and prostate cancer risk: results from two large nested case-control studies

Chronic inflammation has been hypothesized to increase prostate cancer risk. Prostaglandin-endoperoxide synthase 2 (PTGS2) encodes the proinflammatory cyclooxygenase 2 enzyme believed to be the rate-limiting step in the synthesis of prostaglandins, important mediators of inflammation. We investigated associations between PTGS2 polymorphisms and prostate cancer risk among 2321 prostate cancer cases and 2560 controls in two large case-control studies nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Cancer Prevention Study II Nutrition Cohort. Five single nucleotide polymorphisms (SNPs) (rs5277, rs20432, rs4648276, rs5275 and rs689470) were examined in SNP and haplotype analyses (five SNPs in PLCO and four SNPs in the Nutrition Cohort). In PLCO, the Ex10 +837 T>C marker (rs5275) was initially associated with prostate cancer risk (P-trend = 0.02) but became non-significant after adjustment for multiple comparisons (P = 0.08); this SNP showed no association with prostate cancer risk in the Nutrition Cohort (P-trend = 0.54) or in an analysis pooling the two cohorts (P-trend = 0.20). No other SNP was associated with prostate cancer risk in PLCO or the Nutrition Cohort individually or combined. Haplotype analyses suggested an association between PTGS2 variants in PLCO alone (global P = 0.007), but not in the Nutrition Cohort (global P = 0.78) or pooled analysis (global P = 0.18). In conclusion, despite the potential importance of inflammation in prostate carcinogenesis, results from our large study of five PTGS2 SNPs does not support a strong association between PTGS2 variants and prostate cancer risk in non-Hispanic white men.     

Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response

MicroRNAs (miRNA) play important roles in tumorigenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the regulatory effect of miRNAs to their target genes, hence promoting tumorigenesis. This study analyzed 226 single nucleotide polymorphisms (SNP) in miRNA processing genes and miRNA binding sites in 339 ovarian cancer cases and 349 healthy controls to assess association with cancer risk, overall survival, and treatment response. Thirteen polymorphisms were found to have significant association with risk. The most significant were 2 linked SNPs (r(2) = 0.99), rs2740351 and rs7813 in GEMIN4 [odds ratio (OR) = 0.71; 95% confidence interval (CI), 0.57-0.87 and OR = 0.71; 95% CI, 0.57-0.88, respectively]. Unfavorable genotype analysis showed the cumulative effect of these 13 SNPs on risk (P for trend < 0.0001). Potential higher order gene-gene interactions were identified, which categorized patients into different risk groups according to their genotypic signatures. In the clinical outcome study, 24 SNPs exhibited significant association with overall survival and 17 SNPs with treatment response. Notably, patients carrying a rare homozygous genotype of rs1425486 in PDGFC had poorer overall survival [hazard ratio (HR) = 2.69; 95% CI, 1.67-4.33] and worse treatment response (OR = 3.38; 95% CI, 1.39-8.19), compared to carriers of common homozygous and heterozygous genotypes. Unfavorable genotype analyses also showed a strong gene-dosage effect with decreased survival and increased risk of treatment nonresponse in patients with greater number of unfavorable genotypes (P for trend < 0.0001). Taken together, miRNA-related genetic polymorphisms may impact ovarian cancer predisposition and clinical outcome both individually and jointly.     

Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.     

Tagging single nucleotide polymorphisms in MBD4 are associated with risk of lung cancer in a Chinese population

MBD4 (methyl-CpG binding domain protein 4) was identified as a methyl-CpG binding protein and plays an important role in DNA methylation and carcinogenesis. We hypothesized that genetic variants in MBD4 were associated with lung cancer risk. We selected and genotyped three tagging SNPs (rs2311394, rs140693, and rs2005618) of MBD4 using the illumina SNP genotyping BeadLab platform in a case-control study of 500 incident lung cancer patients and 517 cancer-free controls in a Chinese population. We observed a significantly decreased risk of lung cancer associated with the rs140693 GA genotype (adjusted OR=0.70, 95% CI=0.52-0.93), and the combined rs140693 GA/AA variant genotypes (adjusted OR=0.76, 95% CI=0.58-1.00), compared with the wild-type homozygote rs140693 GG. The reduced lung cancer risk in non-smokers carrying rs140693 GA/AA genotypes was more predominant (adjusted OR=0.56, 95% CI=0.35-0.87). However, there was no statistic evidence of gene-smoking interaction. These findings suggest that genetic variants of MBD4 rs140693 may modulate risk of lung cancer. Further larger case-control and functional studies are needed to validate these findings.     

Comprehensive pathway-based association study of DNA repair gene variants and the risk of nasopharyngeal carcinoma

DNA repair plays a central role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether DNA gene variants were associated with nasopharyngeal carcinoma (NPC) risk, a candidate gene association study was conducted among the Cantonese population within the Guangdong Province, China, the ethnic group with the highest risk for NPC. A 2-stage study design was utilized. In the discovery stage, 676 tagging SNPs covering 88 DNA repair genes were genotyped in a matched case-control study (cases/controls = 755/755). Eleven SNPs with P(trend) < 0.01 were identified. Seven of these SNPs were located within 3 genes, RAD51L1, BRCA2, and TP53BP1. In the validation stage, these 11 SNPs were genotyped in a separate Cantonese population (cases/controls = 1,568/1,297). Two of the SNPs (rs927220 and rs11158728), both in RAD51L1, remained strongly associated with NPC. The SNP rs927220 had a significant P(combined) of 5.55 × 10(-5), with OR = 1.20 (95% CI = 1.10-1.30), Bonferroni corrected P = 0.0381. The other SNP (rs11158728), which is in strong linkage disequilibrium with rs927220 (r(2) = 0.7), had a significant P(combined) of 2.0 × 10(-4), Bonferroni corrected P = 0.1372. Gene-environment interaction analysis suggested that the exposures of salted fish consumption and cigarette smoking had potential interactions with DNA repair gene variations, but need to be further investigated. Our findings support the notion that DNA repair genes, in particular RAD51L1, play a role in NPC etiology and development.