151例儿童低级别胶质瘤的表达谱揭示了与位置和组织学亚型相关的分子差异。
Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype.
作者信息
Bergthold Guillaume, Bandopadhayay Pratiti, Hoshida Yujin, Ramkissoon Shakti, Ramkissoon Lori, Rich Benjamin, Maire Cecile L, Paolella Brenton R, Schumacher Steven E, Tabak Barbara, Ferrer-Luna Ruben, Ozek Memet, Sav Aydin, Santagata Sandro, Wen Patrick Yung, Goumnerova Liliana C, Ligon Azra H, Stiles Charles, Segal Rosalind, Golub Todd, Grill Jacques, Ligon Keith L, Chan Jennifer A, Kieran Mark W, Beroukhim Rameen
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts (G.B., P.B., B.R.P., S.E.S., B.T., R.F.-L., C.S., R.S., R.B.); Broad Institute, Cambridge, Massachusetts (G.B., P.B., B.R.P., S.E.S., B.T., R.F.-L., T.G., R.B.); Pediatric Neuro-Oncology Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (P.B., L.C.G., M.W.K.); Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York (Y.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.R., S.S., P.Y.W., A.H.L., K.L.L., J.A.C.); Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.R., L.R., B.R., C.L.M., K.L.L.); Department of Neurosurgery, Acibadem University Medical Center, Istanbul, Turkey (M.O.); Department of Pathology, Acibadem University Medical Center, Istanbul, Turkey (A.S.); Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts (L.C.G.); Departement de Cancerologie de l'enfant et de l'adolescent, Gustave Roussy and Unité Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Université Paris-Sud, Villejuif, France (J.G.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
出版信息
Neuro Oncol. 2015 Nov;17(11):1486-96. doi: 10.1093/neuonc/nov045. Epub 2015 Mar 29.
BACKGROUND
Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity.
METHODS
We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain.
RESULTS
Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. "Not otherwise specified" (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs.
CONCLUSION
Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related.
背景
小儿低级别胶质瘤（PLGGs）是最常见的小儿脑肿瘤，是一组异质性疾病。最近的基因组分析表明，这些肿瘤大多由丝裂原活化蛋白激酶（MAPK）通路改变驱动。然而，对于其临床和组织学异质性所固有的分子特征知之甚少。
方法
我们对151例来自不同部位、年龄和组织学类型的石蜡包埋PLGGs进行了基因表达谱分析。使用无监督和有监督分析，我们将分子特征与年龄、部位、组织学和BRAF基因组状态进行了比较。我们将分子差异与正常小儿脑表达谱进行比较，以观察这些模式是否在正常脑中得到反映。
结果
无监督聚类区分出3个与脑内位置和组织学亚型相关的分子组。“未另作说明”（NOS）肿瘤并不构成一个统一的类别。与幕下肿瘤相比，幕上毛细胞型星形细胞瘤（PAs）显著富集了与炎症活动相关通路的基因。基于肿瘤位置的差异在正常脑组织内的位置依赖性表达差异中未得到反映。我们发现幕上PAs与弥漫性星形细胞瘤之间以及幕上PAs与胚胎发育不良性神经上皮肿瘤之间存在显著差异，但幕上PAs与神经节胶质瘤之间没有差异。儿童和青少年PAs之间观察到相似的表达模式。我们发现BRAF重复型和V600E突变型肿瘤之间存在差异，但原发性和复发性PLGGs之间没有差异。
结论
PLGGs的表达谱揭示了与肿瘤位置、组织学和BRAF基因组状态相关的显著差异。特别是幕上PAs富含似乎与肿瘤相关的炎症通路。
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