| 1. |
- Wang, Zhaoming, et al.
(author)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Jacobs, Kevin B, et al.
(author)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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In: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Journal article (peer-reviewed)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.
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| 3. |
- Schumacher, Fredrick R., et al.
(author)
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Genome-wide association study identifies new prostate cancer susceptibility loci
- 2011
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In: Human Molecular Genetics. - London : IRL Press. - 0964-6906 .- 1460-2083. ; 20:19, s. 3867-3875
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Journal article (peer-reviewed)abstract
- Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
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| 4. |
- Purdue, Mark P, et al.
(author)
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Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:1, s. 60-65
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Journal article (peer-reviewed)abstract
- We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.
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| 5. |
- Wu, Xifeng, et al.
(author)
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A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:2, s. 456-462
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Journal article (peer-reviewed)abstract
- Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 x 10(-10) and P = 6.07 x 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
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| 6. |
- Cao, Yin, et al.
(author)
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Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival
- 2014
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 106:5
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Journal article (peer-reviewed)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.
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| 7. |
- Shui, Irene M., et al.
(author)
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Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
- 2014
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In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 65:6, s. 1069-1075
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Journal article (peer-reviewed)abstract
- Background: Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). Objective: To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. Design, setting, and participants: We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred. Outcome measurements and statistical analysis: The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. Results and limitations: Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. Conclusions: Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. Patient summary: In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 8. |
- Tsilidis, Konstantinos K., et al.
(author)
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Insulin-like growth factor pathway genes and blood concentrations, dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2013
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In: International Journal of Cancer. - Hoboken, NJ, USA : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 133:2, s. 495-504
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Journal article (peer-reviewed)abstract
- It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested casecontrol studies within large North-American and European cohorts. Per-allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (p<0.01), but not with IGFBP-3 concentrations (p>0.10) or with risk of prostate cancer (p>0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance [SSTR5 (somatostatin receptor 5)-rs197056 (uncorrected p for interaction, 0.001); SSTR5-rs197057 (uncorrected p for interaction, 0.002)]. We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein.
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| 9. |
- Leenders, Max, et al.
(author)
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Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4
- 2013
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In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 24:3, s. 595-602
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Journal article (peer-reviewed)abstract
- The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (< 0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
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| 10. |
- Lindstroem, Sara, et al.
(author)
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Replication of five prostate cancer loci identified in an Asian population-results from the NCI breast and prostate cancer cohort consortium (BPC3)
- 2012
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In: Cancer Epidemiology, Biomarkers and Prevention. - Philadelphia : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:1, s. 212-216
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Journal article (peer-reviewed)abstract
- Background: A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry. Methods: We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset. Results: Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 x 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62). Conclusions: Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent. Impact: This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups. Cancer Epidemiol Biomarkers Prev; 21(1); 212-16. (C) 2011 AACR.
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