Human GBM tumor vs Normal Human DNA. Homo sapiens

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the cancer process. Here, we engineered lymphoma-prone mice with chromosomal instability to assess the utility of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Integrating with targeted re-sequencing, our comparative oncogenomic studies efficiently identified FBXW7 and PTEN as commonly deleted or mutated tumor suppressors in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). More generally, the murine cancers acquire widespread recurrent clonal amplifications and deletions targeting loci syntenic to alterations present in not only human T-ALL but also diverse tumors of hematopoietic, mesenchymal and epithelial types. These results thus support the view that murine and human tumors experience common biological processes driven by orthologous genetic events as they evolve towards a malignant phenotype. The highly concordant nature of genomic events encourages the use of genome unstable murine cancer models in the discovery of biologically relevant driver events in human cancer. Keywords: comparative genomic hybridization Overall design: 38 human GBM samples were analyzed. Normal Human DNA was used as reference. Some samples were hybridized with dye-swap replica.

高度重排且发生突变的癌症基因组，在识别驱动癌症发生的致病事件时面临重大挑战。本研究构建了携带染色体不稳定性的易患淋巴瘤小鼠模型，用于评估小鼠模型在癌症基因发现中的应用价值，以及癌症相关拷贝数畸变（copy number aberrations）的跨物种重叠程度。结合靶向重测序技术，本研究的比较肿瘤基因组学分析高效鉴定出FBXW7与PTEN是人类T细胞急性淋巴细胞白血病/淋巴瘤（T-cell acute lymphoblastic leukemia/lymphoma, T-ALL）中常见缺失或突变的肿瘤抑制基因。更广泛地说，小鼠肿瘤会出现广泛的复发性克隆扩增与缺失，其靶向的基因座不仅与人类T-ALL中的变异存在同线性关联，还与造血系统、间充质及上皮来源的多种人类肿瘤中的变异存在同线性关联。因此，本研究结果支持这一观点：小鼠与人类肿瘤在向恶性表型演进的过程中，会经历由同源遗传事件驱动的共同生物学过程。基因组事件的高度一致性，支持使用基因组不稳定的小鼠肿瘤模型以发现人类癌症中具有生物学意义的驱动事件。关键词：比较基因组杂交（comparative genomic hybridization）实验设计概述：共分析38例人类胶质母细胞瘤（Glioblastoma Multiforme, GBM）样本，以正常人类DNA作为参照。部分样本采用染料交换重复实验进行杂交。