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- Garcia-Closas, Montserrat, et al.
(författare)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Rocheleau, T., et al.
(författare)
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Emergence of protocellular growth laws
- 2007
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Ingår i: Philosophical Transactions of the Royal Society B: Biological Sciences. - : The Royal Society. - 1471-2970 .- 0962-8436. ; 362:1486, s. 1841-1845
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Tidskriftsartikel (refereegranskat)abstract
- Template-directed replication is known to obey a parabolic growth law due to product inhibition ( Sievers & Von Kiedrowski 1994 Nature 369, 221; Lee et al. 1996 Nature 382, 525; Varga & Szathmary 1997 Bull. Math. Biol. 59, 1145). We investigate a template-directed replication with a coupled template catalysed lipid aggregate production as a model of a minimal protocell and show analytically that the autocatalytic template-container feedback ensures balanced exponential replication kinetics; both the genes and the container grow exponentially with the same exponent. The parabolic gene replication does not limit the protocellular growth, and a detailed stoichiometric control of the individual protocell components is not necessary to ensure a balanced gene-container growth as conjectured by various authors ( Ganti 2004 Chemoton theory). Our analysis also suggests that the exponential growth of most modern biological systems emerges from the inherent spatial quality of the container replication process as we show analytically how the internal gene and metabolic kinetics determine the cell population's generation time and not the growth law ( Burdett & Kirkwood 1983 J. Theor. Biol. 103, 11-20; Novak et al. 1998 Biophys. Chem. 72, 185-200; Tyson et al. 2003 Curr. Opin. Cell Biol. 15, 221-231). Previous extensive replication reaction kinetic studies have mainly focused on template replication and have not included a coupling to metabolic container dynamics ( Stadler et al. 2000 Bull. Math. Biol. 62, 1061-1086; Stadler & Stadler 2003 Adv. Comp. Syst. 6, 47). The reported results extend these investigations. Finally, the coordinated exponential gene-container growth law stemming from catalysis is an encouraging circumstance for the many experimental groups currently engaged in assembling self-replicating minimal artificial cells
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