50 research outputs found
Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer
Background: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist.Methods: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA.Results: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment- wise test for association (P-heterogeneity = 0.051; P-trend = 0.068).Conclusion: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs
Association between Common Germline Genetic Variation in 84 Candidate Genes/Regions and Risks of Ovarian Cancer.
Background: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. Methods: We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. Results: After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). Conclusion: These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs
YKL-40 tissue expression and plasma levels in patients with ovarian cancer
<p>Abstract</p> <p>Background</p> <p>YKL-40 (chitinase-3-like-1) is a member of "mammalian chitinase-like proteins". The protein is expressed in many types of cancer cells and the highest plasma YKL-40 levels have been found in patients with metastatic disease, short recurrence/progression-free intervals, and short overall survival. The aim of the study was to determine the expression of YKL-40 in tumor tissue and plasma in patients with borderline ovarian tumor or epithelial ovarian cancer (OC), and investigate prognostic value of this marker.</p> <p>Methods</p> <p>YKL-40 protein expression was determined by immunohistochemistry in tissue arrays from 181 borderline tumors and 473 OC. Plasma YKL-40 was determined by ELISA in preoperative samples from 19 patients with borderline tumor and 76 OC patients.</p> <p>Results</p> <p>YKL-40 protein expression was found in cancer cells, tumor associated macrophages, neutrophils and mast cells. The tumor cell expression was higher in OC than in borderline tumors (p = 0.001), and associated with FIGO stage (p < 0.0001) and histological subtype (p = 0.0009). Positive YKL-40 expression (≥ 5% staining) was not associated with reduced survival. Plasma YKL-40 was also higher in patients with OC than in patients with borderline tumors (p < 0.0001), and it was positively correlated to serum CA-125 (p < 0.0001) and FIGO stage (p = 0.0001). Univariate Cox analysis of plasma YKL-40 showed association with overall survival (p < 0.0001). Multivariate Cox analysis, including plasma YKL-40, serum CA125, FIGO stage, age and radicality after primary surgery as variables, showed that elevated plasma YKL-40 was associated with a shorter survival (HR = 2.13, 95% CI: 1.40–3.25, p = 0.0004).</p> <p>Conclusion</p> <p>YKL-40 in OC tissue and plasma are related to stage and histology, but only plasma YKL-40 is a prognostic biomarker in patients with OC.</p
Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer
Low–moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in ∼1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted Pdominant=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case–control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80–0.99) and remained statistically significant (Pdominant=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (Pglobal=0.034) and a haplotype in BRAF that had a protective effect (Pglobal=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC
Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study
Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case–control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01–1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07–1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function
A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2
Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk1. We performed a genome wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ~2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P<10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls confirming its association (combined data odds ratio = 0.82 95% CI 0.79 – 0.86, P-trend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77 95% CI 0.73 – 0.81, Ptrend = 4.1 × 10−21)
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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
Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women
Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNPs) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (p=0.002) with a <25% chance of being a false positive finding (q-value=0.240). Using a multivariate model search algorithm over eleven IL18 tagging SNPs, we found the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (OR=1.24, 95% CI: 1.06, 1.45). In a replication stage, twelve independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (OR=0.99, 95% CI: 0.94, 1.05) when data from the twelve OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial NCO data. This analysis demonstrates the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes