Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer
Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer
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DOI：
10.1073/pnas.0704652104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
--
作者：
Shen, Lanlan;Toyota, Minoru;Issa, Jean-Pierre J.
结肠癌被认为是遗传和表观遗传异常逐渐积累的结果。然而，这一观点并不能完全反映该病的分子异质性。我们分析了97例原发结直肠癌患者的遗传(BRAF、KRAS和P53突变和微卫星不稳定性)和表观遗传学改变(27个CpG岛启动子区的DNA甲基化)。在表观遗传图谱或遗传和表观遗传图谱相结合的基础上进行了两次聚类分析，以识别具有不同分子特征的亚类。DNA甲基化数据的无监督等级聚类确定了三组不同的结肠癌，分别命名为CpG岛甲基化表型(CIMP)1、CIMP2和CIMP阴性。从基因上讲，这三个群体对应着非常不同的特征。CIMP1的特点是MSI(80%)和BRAF突变(53%)以及罕见的KRAS和P53突变(分别为16%和11%)。CIMP2与92%的KRAS突变和罕见的MSI、BRAF或P53突变(分别为0、4和31%)相关。CIMP阴性组P53突变率高(71%)，MSI低(12%)，BRAF或KRAS突变低(33%)。基于遗传和表观遗传参数的聚类还确定了三个不同的(和同类的)群体，这些群体与以前的分类基本重叠。这三个组与年龄、性别或分期无关，但CIMP1和2在近端肿瘤中更常见。综上所述，我们的综合遗传和表观遗传学分析显示，结肠癌对应于三种分子上不同的疾病亚类。
Colon cancer has been viewed as the result of progressive accumulation of genetic and epigenetic abnormalities. However, this view does not fully reflect the molecular heterogeneity of the disease. We have analyzed both genetic (mutations of BRAF, KRAS, and p53 and microsatellite instability) and epigenetic alterations (DNA methylation of 27 CpG island promoter regions) in 97 primary colorectal cancer patients. Two clustering analyses on the basis of either epigenetic profiling or a combination of genetic and epigenetic profiling were performed to identify subclasses with distinct molecular signatures. Unsupervised hierarchical clustering of the DNA methylation data identified three distinct groups of colon cancers named CpG island methylator phenotype (CIMP) 1, CIMP2, and CIMP negative. Genetically, these three groups correspond to very distinct profiles. CIMP1 are characterized by MSI (80%) and BRAF mutations (53%) and rare KRAS and p53 mutations (16% and 11 %, respectively). CIMP2 is associated with 92% KRAS mutations and rare MSI, BRAF, or p53 mutations (0, 4, and 31 % respectively). CIMP-negative cases have a high rate of p53 mutations (71 %) and lower rates of MSI (12%) or mutations of BRAF (2%) or KRAS (33%. Clustering based on both genetic and epigenetic parameters also identifies three distinct (and homogeneous) groups that largely overlap with the previous classification. The three groups are independent of age, gender, or stage, but CIMP1 and 2 are more common in proximal tumors. Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease.