Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles.
Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles.
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DOI：
10.1186/s40478-016-0287-6
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发表时间：
2016-02-29
影响因子：
7.1
通讯作者：
Buslei R
中科院分区：
文献类型：
--
作者：
Hölsken A;Sill M;Merkle J;Schweizer L;Buchfelder M;Flitsch J;Fahlbusch R;Metzler M;Kool M;Pfister SM;von Deimling A;Capper D;Jones DT;Buslei R
颅咽管瘤是一种罕见的鞍区上皮性肿瘤。两个亚型，adamantinomatous（adaCP）和乳头状CP（papCP），以前确定的基础上组织形态学和流行病学方面。最近的数据表明，这两种变体都是由特定的遗传改变定义的，并受到不同的分子途径和特定起源的影响。CP是一种不常见的肿瘤实体，这一事实使得对大型队列的研究变得困难和特殊。为了获得进一步的见解区分CP变体，我们进行了全基因组甲基化（450 k阵列）和基于微阵列的基因表达研究，除了使用80个adaCP和35个papCP的综合队列进行CTNNB 1和BRAF突变分析。BRAFV 600 E突变仅在papCP亚组中发现，在adaCP样品中未检测到。相反，CTNNB 1突变仅在adaCP中检测到。甲基化指纹将DNA标本分配到实体特异性组（papCP（n = 18）; adaCP（n = 25）），与基于组织学的诊断完全匹配，表明它们代表真正不同的生物实体。然而，我们无法在adaCP组（包括11例儿童和14例成人病例）中检测到不同年龄的甲基化特征的显著差异。基于差异基因表达和甲基化的papCP与adaCP组的综合比较显示，adaCP中Wnt和SHH信号通路基因明显上调。因此，AdaCP和papCP代表了不同的肿瘤亚型，它们具有相互排斥的基因突变和甲基化模式，进一步反映在基因表达的差异中。这项研究表明，DNA甲基化分析是一种额外的方法来分类CP到亚型，并暗示了各自的CP变体的发生中的表观遗传机制的作用。检测肿瘤特异性信号通路的激活使靶向干预成为可能。本文的在线版本（doi：10.1186/s40478-016-0287-6）包含补充材料，可供授权用户使用。
Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP. BRAFV600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP. AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention. The online version of this article (doi:10.1186/s40478-016-0287-6) contains supplementary material, which is available to authorized users.