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  • GENOME-WIDE ASSOCIATION  (14)
  • breast cancer  (7)
  • 11
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; HISTORY ; RISK ; SAMPLE ; TUMOR-NECROSIS-FACTOR ; FAMILY ; BIOMARKERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; HEALTH ; AGE ; WOMEN ; SNP ; cancer risk ; GENOTYPES ; HETEROGENEITY ; FAMILIES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; ESTROGEN ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; ALLELES ; biomarker ; GENOTYPE ; FAMILY-HISTORY ; USA ; CANCER-RISK ; Sample Size ; CONSORTIUM ; ERCC4 ; RECEPTOR STATUS ; PROGESTERONE-RECEPTOR GENE ; CASP8
    Abstract: Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASPIO rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610-6)
    Type of Publication: Journal article published
    PubMed ID: 19423537
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  • 12
    Keywords: CANCER ; EXPRESSION ; RISK ; GENE ; SUSCEPTIBILITY ; breast cancer ; PATTERNS ; risk factors ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; PROGESTERONE-RECEPTOR ; BRCA2 MUTATION CARRIERS ; Risk prediction
    Abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P 〈= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P 〈= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment
    Type of Publication: Journal article published
    PubMed ID: 21596841
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  • 13
    Keywords: CANCER ; RISK ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; VARIANT ; SNPs
    Abstract: The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --〉 A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --〉 G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies
    Type of Publication: Journal article published
    PubMed ID: 17293864
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  • 14
    Keywords: CANCER ; POLYMORPHISMS ; BRCA1 ; GLUCOSE ; MUTATION CARRIERS ; METAANALYSIS ; ALLELES ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; 6Q25.1
    Abstract: A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER) positive tumors. Using data from the Breast Cancer Association Consortium(BCAC) we sought to determine if risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)=0.98) at 14q24.1 (RAD51L1), for up to 46,036 invasive breast cancer cases and 46,930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25,458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per allele- odds ratio (OR) for ER-positive tumors was 1.13, 95%CI=1.10 to 1.16, and for ER-negative tumors OR was 1.03, 95%CI=0.98 to 1.07, case only P-heterogeneity = 7.6x10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P=6.7 x10(-3)) and lobular histology (case-only P =0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 21852249
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  • 15
    Keywords: SUSCEPTIBILITY ; WOMEN ; ORAL-CONTRACEPTIVES ; HISTOLOGIC TYPE ; inflammation ; GENOME-WIDE ASSOCIATION
    Abstract: BACKGROUND: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. METHODS: Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. RESULTS: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet 〈 0.001), parity (Phet 〈 0.01), and tubal ligation (Phet = 0.041). CONCLUSIONS: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880-90. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23462924
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  • 16
    Keywords: APOPTOSIS ; POPULATION ; ACTIVATION ; EPITHELIAL-CELLS ; ORAL-CONTRACEPTIVES ; NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; REPRODUCTIVE FACTORS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOME-WIDE ASSOCIATION ; PELVIC-INFLAMMATORY-DISEASE
    Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1alpha (IL1A) is both regulated by and able to activate NF-kappaB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kappaB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P 〈 2.5 x 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.
    Type of Publication: Journal article published
    PubMed ID: 24272484
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