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Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.

ABSTRACT: Association studies have been widely used to search for common low-penetrance susceptibility alleles to breast cancer in general. However, breast cancer is a heterogeneous disease and it has been suggested that it may be possible to identify additional susceptibility alleles by restricting analyses to particular subtypes. We used data on 710 single nucleotide polymorphisms (SNP) in 120 candidate genes from a large candidate gene association study of up to 4,470 cases and 4,560 controls to compare the results of analyses of "overall" breast cancer with subgroup analyses based on the major clinicopathologic characteristics of breast cancer (stage, grade, morphology, and hormone receptor status). No SNP was highly significant in overall effects analysis. Subgroup analysis resulted in substantial reordering of ranks of SNPs, as assessed by the magnitude of the test statistics, and some associations that were not significant for an overall effect were detected in subgroups at a nominal 5% level adjusted for multiple testing. The most significant association of CCND1 SNP rs3212879 with estrogen receptor-negative tumor types (P = 0.001) did not reach genome-wide significance levels. These results show that it may be possible to detect associations using subgroup analysis that are missed in overall effects analysis. If the associations we found can be replicated in independent studies, they may provide important insights into disease mechanisms in breast cancer.

SUBMITTER: Mavaddat N

PROVIDER: S-EPMC2655077 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.

Mavaddat Nasim N Dunning Alison M AM Ponder Bruce A J BA Easton Douglas F DF Pharoah Paul D PD

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090101 1

Association studies have been widely used to search for common low-penetrance susceptibility alleles to breast cancer in general. However, breast cancer is a heterogeneous disease and it has been suggested that it may be possible to identify additional susceptibility alleles by restricting analyses to particular subtypes. We used data on 710 single nucleotide polymorphisms (SNP) in 120 candidate genes from a large candidate gene association study of up to 4,470 cases and 4,560 controls to compar ...[more]

PMID: 19124506

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Project description:Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran-Armitage trend test (p-trend) and a two-degrees of freedom chi(2) test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 x 10(-5)) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.

Project description:Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case-control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations.

Project description:Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies.To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer.We systematically examined the results of meta-analyses and pooled analyses for genetic polymorphisms and cancer risk published through March 2008.We identified 161 meta-analyses and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: include at least 500 cases, have cancer risk as outcome, not be focused on HLA antigen genetic markers, and be published in English.Information on cancer site, gene name, variant, point estimate and 95% confidence interval (CI), allelic frequency, number of studies and cases, tests of study heterogeneity, and publication bias were extracted by 1 investigator and reviewed by other investigators.These 161 analyses evaluated 344 gene-variant cancer associations and included on average 7.3 studies and 3551 cases (range, 508-19 729 cases) per investigated association. The summary odds ratio (OR) for 98 (28%) statistically significant associations (P value <.05) were further evaluated by estimating the false-positive report probability (FPRP) at a given prior probability and statistical power. At a prior probability level of 0.001 and statistical power to detect an OR of 1.5, 13 gene-variant cancer associations remained noteworthy (FPRP <0.2). Assuming a very low prior probability of 0.000001, similar to a probability assumed for a randomly selected single-nucleotide polymorphism in a genome-wide association study, and statistical power to detect an OR of 1.5, 4 associations were considered noteworthy as denoted by an FPRP value <0.2: GSTM1 null and bladder cancer (OR, 1.5; 95% CI, 1.3-1.6; P = 1.9 x 10(-14)), NAT2 slow acetylator and bladder cancer (OR, 1.46; 95% CI, 1.26-1.68; P = 2.5 x 10(-7)), MTHFR C677T and gastric cancer (OR, 1.52; 95% CI, 1.31-1.77; P = 4.9 x 10(-8)), and GSTM1 null and acute leukemia (OR, 1.20; 95% CI, 1.14-1.25; P = 8.6 x 10(-15)). When the OR used to determine statistical power was lowered to 1.2, 2 of the 4 noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia.In this review of candidate gene association studies, nearly one-third of gene-variant cancer associations were statistically significant, with variants in genes encoding for metabolizing enzymes among the most consistent and highly significant associations.

Project description: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.

Dataset Information

Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.

Publications

Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.

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