http://repub.eur.nl/res/aut/32239/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33695/ 2011-04-01T00:00:00Z In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P = 0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention. http://repub.eur.nl/res/pub/33532/ 2011-02-02T00:00:00Z Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR-than PR+tumors (P =. 001). Nulliparity (P = 3 × 10-6) and increasing age at first birth (P = 2 × 10-9) were less frequent in ER-than in ER+tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER-/PR-than in ER+/PR+tumors (P = 1 × 10-7), whereas obesity in older women (>50 years) was less frequent in PR-than in PR+tumors (P = 6 × 10-4). The triple-negative (ER-/PR-/HER2-) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+or PR+tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P =. 61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P =. 34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P =. 09) or CBP tumors. Conclusion sThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology. http://repub.eur.nl/res/pub/28467/ 2010-11-09T00:00:00Z Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.Conclusions: ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers. http://repub.eur.nl/res/pub/28248/ 2010-09-01T00:00:00Z Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend= 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend= 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. http://repub.eur.nl/res/pub/27606/ 2010-05-01T00:00:00Z Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer. http://repub.eur.nl/res/pub/24688/ 2009-07-01T00:00:00Z BackgroundA recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.Methods2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.ResultsWe found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 × 10-19). The odds ratio was lower than that previously reported (P =. 02) and did not vary by age or ethnicity (all P ≥. 2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10-15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P =. 0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 × 10-14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P =. 00002).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women. http://repub.eur.nl/res/pub/33132/ 2009-05-01T00:00:00Z Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 × 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 × 10-8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q. http://repub.eur.nl/res/pub/30480/ 2008-04-01T00:00:00Z A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10-8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.