卵巢癌和子宫内膜癌的差异分析确定了一种甲基化表型。

Differential analysis of ovarian and endometrial cancers identifies a methylator phenotype.

机构信息

DIR/GTB Genomic Functional Analysis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

出版信息

PLoS One. 2012;7(3):e32941. doi: 10.1371/journal.pone.0032941. Epub 2012 Mar 5.

Abstract

Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.

摘要

尽管在过去 30 年中取得了改善,但诊断为上皮性卵巢癌的女性中只有不到一半能在诊断后活过五年。尽管上皮性卵巢癌通常被视为一种单一的疾病,但它包括几种不同的组织学亚型,如乳头状浆液性和子宫内膜样癌。为了确定这些癌中所见的形态学差异是否代表分子水平上的不同特征,我们分析了 11 例乳头状浆液性肿瘤、9 例子宫内膜样卵巢肿瘤、4 例正常输卵管样本和 6 例正常子宫内膜组织,以及 8 例来自 TCGA 的正常输卵管和 4 例浆液性样本。为了在子宫内膜样亚型内进行比较,我们还添加了 6 例原发性子宫子宫内膜样肿瘤和 5 例从子宫转移到卵巢的子宫内膜样转移瘤。数据来自于 27578 个 CpG 二核苷酸,这些二核苷酸位于或靠近 14495 个基因的启动子区域内。我们发现了 36 个在浆液性肿瘤和正常输卵管样本比较中出现甲基化显著增加或减少的位置。此外,应用于所有样本的无监督聚类技术显示出三种主要的图谱,主要由正常样本、浆液性肿瘤和子宫内膜样肿瘤组成,包括卵巢、子宫和转移性起源。聚类分析确定了浆液性组和正常组之间的 60 个差异甲基化位点。一组不相关的 25 例浆液性肿瘤验证了甲基化模式的可重复性。相比之下,子宫内膜样肿瘤和正常样本之间有超过 1000 个基因的甲基化差异。这一发现与一个由甲基化表型引起的普遍的调控破坏一致。通过 DNA 甲基化分析,我们已经确定了与卵巢癌病因学相关的具有已知作用的基因,而途径分析为新基因的作用提供了生物学见解。我们发现浆液性和子宫内膜样卵巢肿瘤之间的差异表明,可以开发干预策略来专门针对上皮性卵巢癌的亚型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7620/3293923/aa4e98e1b28f/pone.0032941.g001.jpg

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