Flynn Aidan, Dwight Trisha, Harris Jessica, Benn Diana, Zhou Li, Hogg Annette, Catchpoole Daniel, James Paul, Duncan Emma L, Trainer Alison, Gill Anthony J, Clifton-Bligh Roderick, Hicks Rodney J, Tothill Richard W
The Peter MacCallum Cancer Centre (A.F., A.H., P.J., A.T., R.J.H., R.W.T.), East Melbourne, Victoria, 3002 Australia; The Department of Pathology (R.W.T., A.F.), University of Melbourne, Parkville, Victoria 3010, Australia; Cancer Genetics (T.D., D.B., R.C.-B.), Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia; University of Sydney (T.D., D.B., A.J.G., R.C.-B.), Sydney, New South Wales 2006, Australia; The University of Queensland Diamantina Institute, Translational Research Institute (J.H., E.L.D.), Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia; The Tumor Bank (L.Z., D.C.), Children's Cancer Research Unit, The Children's Hospital at Westmead, St Westmead, New South Wales 2145, Australia; The Sir Peter MacCallum Department of Oncology (P.J., A.T., R.J.H.), University of Melbourne, Parkville, Victoria 3010, Australia; Department of Endocrinology (E.L.D.), Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia; Royal Melbourne Hospital and Department of Medicine (A.T.), University of Melbourne, Parkville, Victoria 3010, Australia; and Cancer Diagnosis and Pathology Group (A.J.G.), Kolling Institute of Medical Research and the Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
J Clin Endocrinol Metab. 2016 Mar;101(3):1034-43. doi: 10.1210/jc.2015-3889. Epub 2016 Jan 21.
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. OBJECTIVE: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. DESIGN: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. RESULTS: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. CONCLUSIONS: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.
背景:嗜铬细胞瘤和副神经节瘤(PPGLs)是遗传性肿瘤,可根据其潜在的特定遗传驱动因素分为基因表达亚型。 目的:本研究旨在开发一种诊断和研究工具(Pheo-type),能够将PPGL肿瘤分类为基因表达亚型,用于指导和解释基因检测、确定监测方案,并有助于阐明PPGL生物学特性。 设计:使用代表205个PPGL肿瘤的已发表微阵列数据汇编来选择亚型特异性基因,然后将其转化为纳米孔基因表达平台。在微阵列数据集上训练支持向量机,然后在代表38例已知基因型(RET、NF1、TMEM127、MAX、HRAS、VHL和SDHx)的家族性和散发性PPGL病例的独立纳米孔数据集上进行测试。比较了涉及三到六个亚型的不同分类器模型的判别潜力。 结果:选择了一个由46个基因和六个内参组成的基因集,代表六个已知的PPGL亚型;RTK1-3(RET、NF1、TMEM127和HRAS)、MAX样、VHL和SDHx。在38个测试病例中,基于已知基因型与基因表达亚型的关联,34个(90%)被正确预测为六个亚型。从训练中去除以肿瘤和正常肾上腺皮质混合为特征的RTK2亚型,提高了分类准确性(35/38)。将RTK和假低氧PPGL亚型合并为四类然后三类结构,提高了临床应用的分类准确性。 结论:Pheo-type基因表达检测是一种使用常规诊断肿瘤样本预测PPGL基因型的可靠方法。
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