Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors have Genetic Alterations Similar to Human Cancers

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell-to-cell within a single tumor. Using array CGH (aCGH) we found that, as in human cancers, certain fish chromosomes are preferentially over-represented while others are under-represented in many MPNSTs. In addition, we detected evidence for recurrent sub-chromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. One striking amplification included the c-met proto-oncogene. Our results suggest that the zebrafish may be a valuable model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors. For GSM587250-GSM587255: This Illumina sequencing data is for validation of a larger array-CGH dataset (GSM580580-GSM580621). For GSM580580-GSM580621: Two-condition (x3) experiment: (1) genomic DNA: MPNST (rp gene mutation) vs normal tail : 31 replicates; (2) MPNST (p53 mutation) vs normal tail: 5 replicates; (3) normal tail vs. normal tail (6 replicates) For GSM587250-GSM587255: Six samples total, in three pairs of tumor (MPNST) and normal tail control

非整倍体（aneuploidy）是人类癌症的标志性特征之一，但多数小鼠癌症模型难以重现人类多数肿瘤中广泛存在的非整倍体表型。斑马鱼正逐渐成为癌症研究的热门模型动物。本研究报道，斑马鱼中因核糖体蛋白（rp）基因或p53突变诱发的恶性外周神经鞘瘤（MPNSTs）具有高度非整倍体特征。核型分析显示，此类肿瘤多呈现近三倍体的染色体数目，且同一肿瘤内不同细胞的染色体数目存在个体差异。通过阵列比较基因组杂交（array CGH, aCGH）技术，我们发现与人类癌症类似，多数MPNSTs中部分鱼类染色体呈现优先扩增，而另一些染色体则发生缺失。此外，我们还检测到反复出现的亚染色体区域扩增与缺失事件，这些区域可能包含参与癌症起始或进展的关键基因，其中一处显著扩增区域包含c-met原癌基因。本研究结果表明，斑马鱼可作为研究人类癌症中非整倍体现象的优质模型，亦有望用于筛选在鱼类乃至人类肿瘤中发挥驱动作用的候选基因。

针对GSM587250-GSM587255：该Illumina测序数据用于验证更大规模的阵列比较基因组杂交数据集（GSM580580-GSM580621）。
针对GSM580580-GSM580621：该数据集为双条件重复实验（每组设置3次重复）：(1) 核糖体蛋白基因突变型MPNST基因组DNA vs 正常尾鳍基因组DNA：共31次重复；(2) p53基因突变型MPNST基因组DNA vs 正常尾鳍基因组DNA：共5次重复；(3) 正常尾鳍基因组DNA vs 正常尾鳍基因组DNA：共6次重复。
针对GSM587250-GSM587255：共计6个样本，分为3组配对样本，每组包含肿瘤（MPNST）样本与正常尾鳍对照样本。