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  • ASSOCIATION  (4)
  • TUMORS  (4)
  • PROSTATE-CANCER  (3)
  • BREAST-CANCER RISK  (2)
Keywords
  • 1
    Keywords: TUMORS ; polymorphism ; VARIANTS ; BREAST-CANCER ; BRCA1 ; WOMEN ; HETEROZYGOSITY ; MUTATIONS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; LOCUS ; GENOME-WIDE ASSOCIATION ; association studies ; Meiosis ; risk of ovarian cancer
    Abstract: Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer
    Type of Publication: Journal article published
    PubMed ID: 20635389
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  • 2
    Keywords: ASSOCIATION ; POLYMORPHISMS ; VARIANTS ; IDENTIFICATION ; METAANALYSIS ; LOCUS
    Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 x 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 x 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 x 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 x 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 x 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 24764580
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  • 3
    Keywords: RISK ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; statistics ; inflammation ; CARD11 ; FAMILY MEMBERS ; BCL10
    Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-kappaB (NF-kappaB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-kappaB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P 〈 2.5 x 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 x 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 x 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 x 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 x 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
    Type of Publication: Journal article published
    PubMed ID: 24740199
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  • 4
    Keywords: GENES ; MOLECULAR CHARACTERIZATION ; TUMORS ; COLORECTAL-CANCER ; BREAST-CANCER RISK ; HEPATITIS-C ; CELL-TYPE ; ANALYSES REVEAL ; IDENTIFIES SUSCEPTIBILITY LOCI ; FALLOPIAN-TUBE
    Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 x 10(-8)), rs711830 at 2q31.1 (P = 7.5 x 10(-12)) and rs688187 at 19q13.2 (P = 6.8 x 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 x 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
    Type of Publication: Journal article published
    PubMed ID: 26075790
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  • 5
    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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  • 6
    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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  • 7
    Keywords: GENE-EXPRESSION ; CELL-CYCLE ; DOWN-REGULATION ; PROSTATE-CANCER ; ESTROGEN-RECEPTOR ; MAMMARY-GLAND ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; GROWTH-FACTOR RECEPTOR-2 ; MULTIPLE LOCI
    Abstract: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
    Type of Publication: Journal article published
    PubMed ID: 23540573
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  • 8
    Keywords: RISK ; PROSTATE-CANCER ; LOCI ; GENOME-WIDE ASSOCIATION ; COMMON VARIANTS ; CLEAR-CELL CARCINOMA ; MODY
    Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 x 10(-10)) and clear cell (rs11651755 OR = 0.77, P = 1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
    Type of Publication: Journal article published
    PubMed ID: 23535649
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  • 9
    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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