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The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. 相似文献
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Tenesa A Farrington SM Prendergast JG Porteous ME Walker M Haq N Barnetson RA Theodoratou E Cetnarskyj R Cartwright N Semple C Clark AJ Reid FJ Smith LA Kavoussanakis K Koessler T Pharoah PD Buch S Schafmayer C Tepel J Schreiber S Völzke H Schmidt CO Hampe J Chang-Claude J Hoffmeister M Brenner H Wilkening S Canzian F Capella G Moreno V Deary IJ Starr JM Tomlinson IP Kemp Z Howarth K Carvajal-Carmona L Webb E Broderick P Vijayakrishnan J Houlston RS Rennert G Ballinger D Rozek L Gruber SB 《Nature genetics》2008,40(5):631-637
In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology. 相似文献
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Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1 总被引:10,自引:0,他引:10
Park YG Zhao X Lesueur F Lowy DR Lancaster M Pharoah P Qian X Hunter KW 《Nature genetics》2005,37(10):1055-1062
We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis. 相似文献
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Shah SP Roth A Goya R Oloumi A Ha G Zhao Y Turashvili G Ding J Tse K Haffari G Bashashati A Prentice LM Khattra J Burleigh A Yap D Bernard V McPherson A Shumansky K Crisan A Giuliany R Heravi-Moussavi A Rosner J Lai D Birol I Varhol R Tam A Dhalla N Zeng T Ma K Chan SK Griffith M Moradian A Cheng SW Morin GB Watson P Gelmon K Chia S Chin SF Curtis C Rueda OM Pharoah PD Damaraju S Mackey J Hoon K Harkins T Tadigotla V Sigaroudinia M Gascard P Tlsty T Costello JF Meyer IM Eaves CJ Wasserman WW 《Nature》2012,486(7403):395-399
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes. 相似文献
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Yokoyama S Woods SL Boyle GM Aoude LG MacGregor S Zismann V Gartside M Cust AE Haq R Harland M Taylor JC Duffy DL Holohan K Dutton-Regester K Palmer JM Bonazzi V Stark MS Symmons J Law MH Schmidt C Lanagan C O'Connor L Holland EA Schmid H Maskiell JA Jetann J Ferguson M Jenkins MA Kefford RF Giles GG Armstrong BK Aitken JF Hopper JL Whiteman DC Pharoah PD Easton DF Dunning AM Newton-Bishop JA Montgomery GW Martin NG Mann GJ Bishop DT Tsao H Trent JM Fisher DE Hayward NK Brown KM 《Nature》2011,480(7375):99-103
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Kote-Jarai Z Olama AA Giles GG Severi G Schleutker J Weischer M Campa D Riboli E Key T Gronberg H Hunter DJ Kraft P Thun MJ Ingles S Chanock S Albanes D Hayes RB Neal DE Hamdy FC Donovan JL Pharoah P Schumacher F Henderson BE Stanford JL Ostrander EA Sorensen KD Dörk T Andriole G Dickinson JL Cybulski C Lubinski J Spurdle A Clements JA Chambers S Aitken J Gardiner RA Thibodeau SN Schaid D John EM Maier C Vogel W Cooney KA Park JY Cannon-Albright L Brenner H Habuchi T Zhang HW Lu YJ Kaneva R 《Nature genetics》2011,43(8):785-791
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. 相似文献
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Common variants in WFS1 confer risk of type 2 diabetes 总被引:10,自引:0,他引:10
Sandhu MS Weedon MN Fawcett KA Wasson J Debenham SL Daly A Lango H Frayling TM Neumann RJ Sherva R Blech I Pharoah PD Palmer CN Kimber C Tavendale R Morris AD McCarthy MI Walker M Hitman G Glaser B Permutt MA Hattersley AT Wareham NJ Barroso I 《Nature genetics》2007,39(8):951-953
We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes. 相似文献
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A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability 总被引:21,自引:0,他引:21
Healey CS Dunning AM Teare MD Chase D Parker L Burn J Chang-Claude J Mannermaa A Kataja V Huntsman DG Pharoah PD Luben RN Easton DF Ponder BA 《Nature genetics》2000,26(3):362-364
Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner. 相似文献