Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Oncogene. 2012 Mar 1;31(9):1095-104. doi: 10.1038/onc.2011.311. Epub 2011 Aug 1.
Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in ~80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.
继发外周性软骨肉瘤是由先前存在的骨软骨瘤恶性转化而来的，而骨软骨瘤是最常见的良性骨肿瘤。骨软骨瘤是由 EXT1 或 EXT2 的遗传异常引起的：EXT1 的纯合缺失特征为散发性骨软骨瘤（非家族性/单发），EXT1 或 EXT2 的种系突变与杂合性丢失相结合定义了遗传性多发性骨软骨瘤。虽然具有 EXT 纯合失活的细胞和野生型细胞形成骨软骨瘤，但继发外周性软骨肉瘤的细胞组成及其形成过程中的 EXT 作用仍不清楚。我们报告使用靶向平铺分辨率寡核苷酸阵列 CGH（阵列比较基因组杂交），在散发性继发外周性软骨肉瘤中，EXT1 或 EXT2 的纯合缺失比基于它们起源于散发性骨软骨瘤的假设更不常见（2/17，12%），在我们的病例中，EXT1 的纯合失活约占 80%。用 EXT1 探针进行的 FISH 证实，与散发性骨软骨瘤不同，来自散发性继发外周性软骨肉瘤的细胞主要保留一个（杂合缺失位点）或两个拷贝（野生型）的 EXT1 基因座。通过免疫组织化学，我们证实了在散发性骨软骨瘤中存在功能失调的 EXT1 细胞，并显示在散发性继发外周性软骨肉瘤中存在功能正常的 EXT1 细胞。这些免疫结果在遗传性多发性骨软骨瘤的背景下得到了验证。因此，我们的数据指向一种致癌模型，其中骨软骨瘤创建了一个龛位，具有功能性 EXT1 的野生型细胞易于获得其他导致继发外周性软骨肉瘤的突变，表明 EXT 独立机制参与了继发外周性软骨肉瘤的发病机制。
