| 1. |
- Ahn, Jiyoung, et al.
(författare)
-
Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3).
- 2009
-
Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 18:19, s. 3749-57
-
Tidskriftsartikel (refereegranskat)abstract
- Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N = 4720), testosterone (N = 4678), 3 alpha-androstanediol-glucuronide (N = 4767) and 17beta-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 x 10(-21)), consistent with previous studies, and testosterone (P = 7.54 x 10(-15)), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 x 10(-6)) and SRD5A2 with 3 alpha-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 x 10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones.
|
|
| 2. |
- Berndt, Sonja I., et al.
(författare)
-
Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
|
|
| 3. |
- Berndt, Sonja I, et al.
(författare)
-
Large-scale fine mapping of the HNF1B locus and prostate cancer risk
- 2011
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3322-3329
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
|
|
| 4. |
- Cao, Yin, et al.
(författare)
-
Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival
- 2014
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 106:5
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr = .04). Prediagnostic IGF1 (HRhighest (vs lowest quartile) = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% Cl = 0.65 to 1.34) levels were not associated with PCa mortality.CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
|
|
| 5. |
- Cerhan, James R., et al.
(författare)
-
Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
-
Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
|
|
| 6. |
- Cox, David G., et al.
(författare)
-
A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2006
-
Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 8:5
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/ or androgen receptor ( AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium ( BPC3). Methods The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships ( blocks) across the gene were then identified, and haplotypetagging single nucleotide polymorphisms ( htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts ( 5,603 breast cancer cases and 7,480 controls). Results We found no association between any genetic variation ( SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. Conclusion Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.
|
|
| 7. |
- Cox, David G, et al.
(författare)
-
Haplotypes of the estrogen receptor beta gene and breast cancer risk
- 2008
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 122:2, s. 387-392
-
Tidskriftsartikel (refereegranskat)abstract
- Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
|
|
| 8. |
- Dossus, Laure, et al.
(författare)
-
PTGS2 and IL6 genetic variation and risk of breast and prostate cancer : results from the Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2010
-
Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 31:3, s. 455-461
-
Tidskriftsartikel (refereegranskat)abstract
- Genes involved in the inflammation pathway have been associated with cancer risk. Genetic variants in the interleukin-6 (IL6) and prostaglandin-endoperoxide synthase-2 (PTGS2, encoding for the COX-2 enzyme) genes, in particular, have been related to several cancer types, including breast and prostate cancers. We conducted a study within the Breast and Prostate Cancer Cohort Consortium to examine the association between IL6 and PTGS2 polymorphisms and breast and prostate cancer risk. Twenty-seven polymorphisms, selected by pairwise tagging, were genotyped on 6292 breast cancer cases and 8135 matched controls and 8008 prostate cancer cases and 8604 matched controls. The large sample sizes and comprehensive single nucleotide polymorphism tagging in this study gave us excellent power to detect modest effects for common variants. After adjustment for multiple testing, none of the associations examined remained statistically significant at P = 0.01. In analyses not adjusted for multiple testing, one IL6 polymorphism (rs6949149) was marginally associated with breast cancer risk (TT versus GG, odds ratios (OR): 1.32; 99% confidence intervals (CI): 1.00-1.74, P(trend) = 0.003) and two were marginally associated with prostate cancer risk (rs6969502-AA versus rs6969502-GG, OR: 0.87, 99% CI: 0.75-1.02; P(trend) = 0.002 and rs7805828-AA versus rs7805828-GG, OR: 1.11, 99% CI: 0.99-1.26; P(trend) = 0.007). An increase in breast cancer risk was observed for the PTGS2 polymorphism rs7550380 (TT versus GG, OR: 1.38, 99% CI: 1.04-1.83). No association was observed between PTGS2 polymorphisms and prostate cancer risk. In conclusion, common genetic variation in these two genes might play at best a limited role in breast and prostate cancers.
|
|
| 9. |
- Gu, Fangyi, et al.
(författare)
-
Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer
- 2010
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 19:11, s. 2877-2887
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.
|
|
| 10. |
- Jacobs, Kevin B, et al.
(författare)
-
Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
-
Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
-
Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
|
|
