Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas
Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas
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DOI：
10.1016/j.jcmgh.2019.04.002
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Whitehall, Vicki
中科院分区：
文献类型：
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作者：
Fennell, Lochlan;Dumenil, Troy;Whitehall, Vicki
背景与目的：结直肠癌是一种表观遗传异质性疾病，但CpG岛甲基化表型(CpG Island omeator表型，CIMP)的范围和谱尚不清楚。方法：应用DNA甲基化和RNA表达谱芯片检测216例未经筛选的结直肠癌组织中CpG岛甲基化和转录水平的表达，并利用癌症基因组图谱450K和RNA测序数据进行验证。使用CIMP亚型癌症基因组图谱外显子评估表观遗传调控基因的突变。结果：CIMP-高分化癌根据甲基化情况分为CIMP-H1和CIMP-H2。KRAS突变与CIMP-H2癌显著相关，但与CIMP-H1癌无关。随着甲基化程度的增加，患者的年龄从CIMP阴性亚组的62岁逐步增加到CIMP-H1亚组的75岁(P<；.0001)。CIMP-H1主要包括共识分子亚型1(70%)，而共识分子亚型3在CIMP-H2亚组中过度表达(55%)。多梳抑制复合体-2(PRC2)标记的基因座在CIMP癌中发生了显著的基因体甲基化(P<；1.6×10(-78))。我们发现了对基因体甲基化敏感的癌基因和抵抗基因体甲基化的Wnt通路拮抗剂。在染色质重塑基因中发现了CIMP簇特异性突变，如Switch/Sucose非发酵型基因家族和Chromodomain helicase DNA结合基因家族。我们发现CIMP与年龄、性别和肿瘤部位显著相关，并确定了基因体甲基化在锯齿状肿瘤进展中的作用。这些数据支持我们最近的发现，即CIMP在年轻患者中并不常见，BRAF突变息肉在年轻患者中恶性进展的可能性可能有限。
BACKGROUND & AIMS: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear.METHODS: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes.RESULTS: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMPnegative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 x 10(-78)). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster-specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families.CONCLUSIONS: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.