结合染色体臂状态和显著异常的基因组位置揭示了新的癌症亚型
Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes
摘要：
许多类型的肿瘤表现出染色体丢失或获得，以及局部扩增和缺失。在任何给定的肿瘤类型中，也观察到样品特异性扩增和缺失。通常，在更多肿瘤中异常或其拷贝数变化更强的区域将被认为是与癌症生物学相关的更有希望的候选者。我们寻求一种直观的方法来定义这种畸变并对其进行优先排序。我们将与像差相关联的体积V定义为三个因子的乘积：具有畸变的患者的分数，b.像差长度和c.其幅度。我们的算法将来自真实数据的V值与通过排列获得的空分布进行比较，并产生V测量值的统计显著性p值。我们检测到显著异常的遗传位置，并将其与染色体臂状态相结合，以创建肿瘤基因组的简洁指纹。该基因组指纹用于可视化肿瘤，突出显示共同发生或相互排斥的事件。我们将该方法应用于髓母细胞瘤和神经母细胞瘤的三个不同的公共阵列CGH数据集，并证明了其检测已知在测试的癌症类型中发生改变的染色体区域的能力，以及建议新的基因组位置进行测试。我们发现了一种潜在的髓母细胞瘤新亚型，类似于神经母细胞瘤1型。
英文摘要：
Many types of tumors exhibit chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletionsare also observed. Typically, a region that is aberrant in more tumors,or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the volume associated with an aberration, as the product of three factors: a. fraction of patients with the aberration, b. the aberrations length and c. its amplitude. Our algorithm compares the values of V derived from real data to a null distribution obtained by permutations, and yields the statistical significance, p value, of the measured value of V. We detected genetic locations that were significantly aberrant and combined them with chromosomal arm status to create a succint fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co ocurring or mutually exclusive. We allpy the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.
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