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  • 1
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; IMPACT ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; polymorphism ; single nucleotide polymorphism ; VARIANTS ; gene expression ; NUMBER ; MUTATION ; genetics ; SNP ; colorectal cancer ; COLORECTAL-CANCER ; REGION ; MUTATIONS ; INDIVIDUALS ; SERIES ; HEALTHY ; heredity ; molecular biology ; molecular ; RE ; VARIANT ; INCREASE ; METAANALYSIS ; ALLELES ; LOCUS ; single-nucleotide polymorphism ; ENGLAND ; 8Q24 ; INCREASES ; GENOME-WIDE ASSOCIATION ; association study ; SCAN ; GENOME-WIDE
    Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; P-trend = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression
    Type of Publication: Journal article published
    PubMed ID: 18753146
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  • 2
    Keywords: COHORT ; VARIANTS ; WOMEN ; HEIGHT ; METAANALYSIS ; bias ; ESTROGEN ; GENOME-WIDE ASSOCIATION ; PROGESTERONE-RECEPTOR STATUS ; INOSITOL POLYPHOSPHATES
    Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int)) 〈1.1 x 10(-3). None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women 170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women 〈160 cm (OR = 0.83, p = 0.039, p(int) = 1.9 x 10(-4)). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 x 10(-4)), and absent in women who had had just one (OR = 0.96, p = 0.19, p(int) = 6.1 x 10(-4)). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 x 10(-5)), but no association was observed in current smokers (OR = 1.07, p = 0.14, p(int) = 3.4 x 10(-4)). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. What's new? The recent discovery of 47 susceptibility loci associated with all or estrogen receptor-negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non-genetic) risk factors influenced the risk assessment. In this gene-environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 25227710
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  • 3
    Keywords: carcinoma ; fibroblasts ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; REVERSE-TRANSCRIPTASE HTERT ; GENETIC-VARIATION ; COMMON VARIANTS ; TERT-CLPTM1L LOCUS ; BUCCAL CELLS
    Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
    Type of Publication: Journal article published
    PubMed ID: 23535731
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  • 4
    Keywords: RISK ; prognosis ; PROGRESSION ; CYCLOPHOSPHAMIDE ; METAANALYSIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; EPIRUBICIN ; LOCI ; GENOME-WIDE ASSOCIATION ; GENOTYPE IMPUTATION
    Abstract: Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37 954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200 000 and 900 000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23 059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
    Type of Publication: Journal article published
    PubMed ID: 25890600
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  • 5
    Keywords: CANCER ; tumor ; MODEL ; NEW-YORK ; RISK ; GENE ; GENES ; TUMORS ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST-CANCER ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; PROSTATE-CANCER ; genotyping ; HIGH-RISK ; REPLICATION ; heredity ; RE ; VARIANT ; SNPs ; METAANALYSIS ; ALLELES ; analysis ; PHASE ; USA ; ENGLAND ; GENOME-WIDE ASSOCIATION ; SCAN ; EIF3S3
    Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P 〈 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping ( 10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P=2.5 x 10(-13) overall; P=6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P=3.3 x 10(-18) overall; P=9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition
    Type of Publication: Journal article published
    PubMed ID: 18372905
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  • 6
    Keywords: CANCER ; SURVIVAL ; tumor ; DIAGNOSIS ; INFORMATION ; DEATH ; EPIDEMIOLOGY ; MORTALITY ; POPULATION ; RISK ; GENE ; microarray ; TUMORS ; validation ; DNA ; RISK-FACTORS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; ASSAY ; microarrays ; OVARIAN-CANCER ; meta-analysis ; SNP ; risk factors ; mass spectrometry ; SPECTROMETRY ; RISK FACTOR ; PROGNOSTIC-FACTORS ; MASS-SPECTROMETRY ; ONCOLOGY ; case-control study ; REGRESSION ; ASSOCIATIONS ; overall survival ; PROGNOSTIC-FACTOR ; METAANALYSIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; cancer survival ; INTERNATIONAL CASE-CONTROL ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIATION ; REPAIR GENES ; TUMOR CHARACTERISTICS ; COMMON POLYMORPHISMS ; single nucleotide ; journals ; COX REGRESSION ; ALL-CAUSE ; BRCA1 MUTATIONS
    Abstract: 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. We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 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 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 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. In 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 x 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 x 10(-4)). The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer
    Type of Publication: Journal article published
    PubMed ID: 20308648
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  • 7
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; SURVIVAL ; tumor ; KINASE ; DIAGNOSIS ; SUPPORT ; DISEASE ; RISK ; DISTINCT ; PROTEIN ; TUMORS ; PROTEIN-KINASE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; prevention ; DIFFERENCE ; genetics ; COLORECTAL-CANCER ; PROSTATE-CANCER ; cancer risk ; PROGNOSTIC-FACTORS ; PROGNOSTIC FACTORS ; PROGNOSTIC FACTOR ; heredity ; KERATINOCYTE GROWTH-FACTOR ; HETEROGENEITY ; fibroblast ; SNPs ; overall survival ; GRADE ; PROGNOSTIC-FACTOR ; METAANALYSIS ; ESTROGEN ; USA ; CANCER-RISK ; comparison ; GENOME-WIDE ASSOCIATION ; LOW-GRADE ; FGFR2 ; NUCLEOTIDE ; genetic variants
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 18437204
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  • 8
    Keywords: CELLS ; DISEASE ; GENE-EXPRESSION ; VARIANTS ; REVEALS ; BREAST-CANCER RISK ; METAANALYSIS ; WIDE ASSOCIATION ; CENTRAL PRECOCIOUS PUBERTY ; HUMAN PREFRONTAL CORTEX
    Abstract: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P 〈 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
    Type of Publication: Journal article published
    PubMed ID: 25231870
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