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    • 2. 发明授权
    • DNA methylation markers associated with the CpG island methylator phenotype (CIMP) in human colorectal cancer
    • 与人结肠直肠癌中CpG岛甲基化表型(CIMP)相关的DNA甲基化标记
    • US08110361B2
    • 2012-02-07
    • US11913535
    • 2006-05-02
    • Peter W. LairdKimberly D. SiegmundMihaela CampanDaniel J. WeisenbergerTiffany I. Long
    • Peter W. LairdKimberly D. SiegmundMihaela CampanDaniel J. WeisenbergerTiffany I. Long
    • C12Q1/68
    • C12Q1/6886C12Q2600/112C12Q2600/154C12Q2600/156C12Q2600/158
    • Particular aspects confirm the existence of a CpG island methylator phenotype (CIMP) in colorectal cancer, and provide novel validated DNA methylation markers associated with CIMP. Additional aspects provide novel methods and compositions for: determining CIMP status in colorectal cancers, determining the relationship between CIMP status and other molecular features of the cancers (e.g., BRAF mutation, KRAS mutation and MSI status); determining the relationship between CIMP status and other variables (e.g., age, sex, tumor location, family history, race, country of origin, tumor characteristics (including, tumor type, tumor grade, invasive margin characteristics, lymphocyte infiltration characteristics, direct spread, lymph node spread, venous spread and type of residual adjacent polyp, if present)); and determining, between subgroups defined by CIMP status and BRAF mutations, effects of selected risk factors (e.g., body mass index, smoking history, alcohol intake, dietary folate intake, folate metabolic enzyme polymorphisms and history of hormonal use).
    • 特异性方面证实了结肠直肠癌中CpG岛甲基化表型(CIMP)的存在,并提供与CIMP相关的新的有效DNA甲基化标记。 另外的方面提供了新的方法和组合物:确定结肠直肠癌中的CIMP状态,确定CIMP状态与癌症的其它分子特征(例如BRAF突变,KRAS突变和MSI状态)之间的关系; 确定CIMP状态与其他变量(如年龄,性别,肿瘤位置,家族史,种族,起源国家,肿瘤特征(包括肿瘤类型,肿瘤等级,浸润性边缘特征,淋巴细胞浸润特征,直接传播, 淋巴结扩散,静脉扩散和残留相邻息肉的类型,如果存在)); 并确定由CIMP状态和BRAF突变所定义的亚组之间,选择的风险因素(例如体重指数,吸烟史,酒精摄入,饮食叶酸摄入,叶酸代谢酶多态性和激素使用史)的影响。
    • 4. 发明申请
    • HIGH THROUGHPUT METHODS COMPRISING ANALYSIS OF REPETITIVE ELEMENT DNA METHYLATION
    • 包含重复元件DNA甲基化分析的高通量方法
    • US20090123915A1
    • 2009-05-14
    • US11719033
    • 2005-11-10
    • Peter W. LairdDaniel J. WeisenbergerMihaela CampanTiffany I. Long
    • Peter W. LairdDaniel J. WeisenbergerMihaela CampanTiffany I. Long
    • C12Q1/68
    • C12Q1/6827C12Q2561/113C12Q2545/114C12Q2531/113
    • Preferred aspects provide novel high-throughput, sensitive methods (e.g., real-time PCR-based (MethyLight™) reactions) for detection and/or measurement of global genomic 5-methylcytosine content, based on measurement of DNA methylation of Alu, LINE-1 repetitive sequences, and the chromosome 1 centromeric satellite alpha and juxtacentromeric satellite 2 repeat sequences. Additional aspects provide sensitive methods for determining the amount of a DNA (e.g., in formalin-fixed, paraffin-embedded tissues). Combined (mean) use of Alu and Sat2 repeat methylation measurements provides for a surprisingly close correlation with global genomic 5-methylcytosine content measurements obtained by HPLC. Methylation of Alu repeats was determined to be closely associated with HPLC-based global methylation levels, as was methylation of satellite 2 and LINE-1 global genomic 5-methylcytosine content. The assays provide surrogate markers for global genomic 5-methylcytosine content analyses, and have substantial utility for high-throughput and population-based studies (e.g., genetic and dietary influences on global DNA methylation, folate deficiency, MTHFR gene polymorphisms, etc).
    • 优选的方面提供新的高通量,敏感的方法(例如,基于实时PCR的(MethyLight TM)反应),用于检测和/或测量全局基因组5-甲基胞嘧啶含量,基于测量Alu的DNA甲基化, LINE-1重复序列,以及1号染色体着丝粒卫星α和juxtacentromeric卫星2重复序列。 另外的方面提供用于确定DNA量的敏感方法(例如,在福尔马林固定的石蜡包埋的组织中)。 Alu和Sat2重复甲基化测量的组合(平均)使用提供了通过HPLC获得的全球基因组5-甲基胞嘧啶含量测量值的令人惊讶的密切相关性。 Alu重复的甲基化被确定为与基于HPLC的全球甲基化水平密切相关,卫星2和LINE-1全局基因组5-甲基胞嘧啶含量的甲基化也是如此。 该测定法为全球基因组5-甲基胞嘧啶含量分析提供替代标记,并且对于高通量和基于人群的研究(例如,对全球DNA甲基化,叶酸缺乏,MTHFR基因多态性等的遗传和饮食影响)具有实用性。