Association Study Of Breast Cancer Research Articles

Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk

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 χ2 test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 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.

Association of gene variants in the transforming growth factor beta signalling pathways with invasive breast cancer risk

We are performing comprehensive association studies of single nucleotide polymorphisms (SNPs) in genes in the transforming growth factor beta (TGFβ) signalling pathways in a female breast cancer case-control study. TGFβ acts as a suppressor of primary tumour initiation but is implicated as a promoter of the later malignant stages. A hypothesis explaining this dual action proposes that TGFβ acts through the ubiquitous ALK5/SMADs2&3 signalling pathway to inhibit proliferation of primary tumour cells, but acts through the endothelial-specific ALK1/SMADs1&5 pathway to promote angiogenesis, which is required for progression to malignancy. In a previous study we showed that a SNP generating a leucine to proline substitution in the signal peptide of the TGFB1 protein was associated with a 1.24-fold increase in the risk of invasive breast cancer, with increased levels of the protein in human serum and with a 2.8-fold increase in amount of the protein secreted in vitro. It is also plausible that other genes in the TGFβ signalling pathways might be associated with altered risk of breast cancer. We have initiated systematic breast cancer association studies with SNPs in the genes encoding proteins directly implicated in TGFβ signalling pathways, including the LTBP and TGFβ isoforms, ALK1, ALK5 and TGFBR2 receptors, and SMADs 1–7. A comprehensive SNP tagging approach was used to select variants for genotyping in a staged study design using up to 4,600 cases and 4,600 controls, all from the East Anglian region of the United Kingdom (>98% of northwestern European ancestry). To date, nine genes (TGFB1, TGFB2, TGFB3, ALK1, ALK5, TGFBR2, Endoglin, SMAD2 and SMAD4) have been analysed. From 285 common SNPs (minor allele frequency >0.05), identified from the International HapMap project data, 83 tagging SNPs have been defined and genotyped. Statistically significant associations with cancer susceptibility have been identified with at least one variant in five of the genes. The TGFB2, TGFB3, Endoglin and SMAD4 genes are not associated. A further eight genes will be studied.

Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes.

BackgroundSubtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFß1, IGFBP3) were evaluated.MethodsGenomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported.ResultsGenotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFß1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P.ConclusionSome variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted.