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A common coding variant in CASP8 is associated with breast cancer risk
Cox, Angela,Dunning, Alison M,Garcia-Closas, Montserrat,Balasubramanian, Sabapathy,Reed, Malcolm W R,Pooley, Karen A,Scollen, Serena,Baynes, Caroline,Ponder, Bruce A J,Chanock, Stephen,Lissowska, Jola Nature Pub. Co 2007 Nature genetics Vol.39 No.3
The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 −202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9–15 studies, comprising 11,391–18,290 cases and 14,753–22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85–0.94) and 0.74 (95% c.i.: 0.62–0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P<SUB>trend</SUB> = 1.1 × 10<SUP>−7</SUP>) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02–1.13) and 1.16 (95% c.i.: 1.08–1.25), respectively; P<SUB>trend</SUB> = 2.8 × 10<SUP>−5</SUP>). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.
Genome-wide association analysis identifies three new breast cancer susceptibility loci
Ghoussaini, Maya,Fletcher, Olivia,Michailidou, Kyriaki,Turnbull, Clare,Schmidt, Marjanka K,Dicks, Ed,Dennis, Joe,Wang, Qin,Humphreys, Manjeet K,Luccarini, Craig,Baynes, Caroline,Conroy, Don,Maranian, Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.3
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ??% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ??0,000 cases and ??8,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 ? 10<SUP>??35</SUP>), 12q24 (rs1292011; P = 4.3 ? 10<SUP>??19</SUP>) and 21q21 (rs2823093; P = 1.1 ? 10<SUP>??12</SUP>). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Stc1: A Critical Link between RNAi and Chromatin Modification Required for Heterochromatin Integrity
Bayne, Elizabeth H.,White, Sharon A.,Kagansky, Alexander,Bijos, Dominika A.,Sanchez-Pulido, Luis,Hoe, Kwang-Lae,Kim, Dong-Uk,Park, Han-Oh,Ponting, Chris P.,Rappsilber, Juri,Allshire, Robin C. Cell Press 2010 Cell Vol.140 No.5
<P><B>Summary</B></P><P>In fission yeast, RNAi directs heterochromatin formation at centromeres, telomeres, and the mating type locus. Noncoding RNAs transcribed from repeat elements generate siRNAs that are incorporated into the Argonaute-containing RITS complex and direct it to nascent homologous transcripts. This leads to recruitment of the CLRC complex, including the histone methyltransferase Clr4, promoting H3K9 methylation and heterochromatin formation. A key question is what mediates the recruitment of Clr4/CLRC to transcript-bound RITS. We have identified a LIM domain protein, Stc1, that is required for centromeric heterochromatin integrity. Our analyses show that Stc1 is specifically required to establish H3K9 methylation via RNAi, and interacts both with the RNAi effector Ago1, and with the chromatin-modifying CLRC complex. Moreover, tethering Stc1 to a euchromatic locus is sufficient to induce silencing and heterochromatin formation independently of RNAi. We conclude that Stc1 associates with RITS on centromeric transcripts and recruits CLRC, thereby coupling RNAi to chromatin modification.</P>
Animal care and use programs: Global Harmonization Through Alternatives
( Kathryn Bayne ) 한국동물실험대체법학회 2007 한국동물실험대체법학회 학술대회집 Vol.2007 No.1
At an accelerating pace, the application of the 3Rs to the design and conduct of animal experiments has spread worldwide in the laboratory animal science community. What was once regarded with some skepticism is now widely viewed as a credible, and indeed scientific, approach to animal-based research. As the principles of reduction, refinement and replacement are more broadly implemented, a natural outcome is that certain procedures are used in preference to others because they enhance both animal welfare and the quality of the data collected, meet the criteria of the 3Rs, have been scientifically validated, and may be more economic. Animal care and use program elements are being harmonized as new research is published on alternative routine experimental procedures and animal husbandry practices. For example, alternative housing environments have been developed for certain species of laboratory animals for which urine and / or feces must be collected through the elimination of metabolic cages, refinements have been made to the cage environment through the provision of environmental enrichment, and animal housing environments have been generally improved through the design of cage equipment that enhances animal well-being. Meetings of experts from around the world have been held to discuss and come to consensus on common practices in the research laboratory, such as euthanasia of rodents by carbon dioxide and alternative methods of husbandry have been published, such as new methods of rodent identification. To facilitate the ongoing search for alternatives which improve laboratory animal welfare and animal research data, international collaboration and communication is essential, and opportunities for this communication and collaboration must continue to be given priority.