Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Mod Pathol. 2014 Apr;27(4):509-15. doi: 10.1038/modpathol.2013.163. Epub 2013 Oct 4.
MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of well-characterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sun-exposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2-3+: 6 cases, 16%; 1+: 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2-3+ immunostaining showed high-level gene amplification. One additional case with 3+ immunostaining showed higher level aneusomy of chromosome 8 (5-8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3-5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.
MYC 是位于 8q24 染色体上的原癌基因，参与细胞增殖和分化的控制。先前的研究记录了放射后血管肉瘤中 MYC 基因的高水平扩增和免疫组化（IHC）过表达，但原发性皮肤血管肉瘤（AS-C）或其他与放射相关的血管增生，如非典型血管病变中没有。受我们最近在原发性肝血管肉瘤中发现 MYC 扩增的启发，我们分析了大量特征明确的 AS-C，以研究 MYC 扩增和蛋白过表达。从我们的档案中检索到 38 例 AS-C 的福尔马林固定、石蜡包埋块，并通过 IHC 分析和荧光原位杂交（FISH）进行检查，使用商业上可获得的抗体和探针。对于 FISH 分析，将 MYC 的拷贝数与对照基因 CEN8（MYC/CEN8 比值）进行比较。所有病例均发生在暴露于阳光的皮肤上；没有患者有治疗性照射的病史。使用对数秩检验评估了生存与各种临床病理变量之间的可能关联。通过 IHC 分析，在 38 例 AS-C 中有 9/38（24%）显示 MYC 过表达（2-3+：6 例，16%；1+：3 例，8%）。通过 FISH 分析，在 2-3+免疫染色的 5 个有信息的病例中有 2/5（40%）显示高水平基因扩增。另外 1 例 3+免疫染色的病例显示 8 号染色体高倍体（5-8 MYC 和 CEN8）。在 14 例 IHC 阴性病例中有 2 例（14%）也携带 MYC 扩增（1 例高水平和 1 例低水平）。无论是否存在 MYC 表达，AS-C 中都观察到 8 号染色体的低拷贝数增益（3-5 MYC 和 CEN8）。MYC 扩增和 MYC 蛋白过表达与临床结果无关。我们首次在皮肤原发性（非放射相关）AS 中显示了 MYC 基因扩增和蛋白过表达。在缺乏基因扩增的病例中，MYC 蛋白过表达可能反映了 MYC 激活的其他机制。研究更多显示 MYC 扩增的 AS-C 可能有必要确定此类病例的行为是否与更常见的非扩增病例不同。
