Division of Hematology, NYU School of Medicine, NYU Langone Cancer Center, NY, USA.
Mutat Res. 2010 Apr 1;686(1-2):1-8. doi: 10.1016/j.mrfmmm.2009.11.012. Epub 2010 Jan 8.
It has been proposed that hypermutability is necessary to account for the high frequency of mutations in cancer. However, historically, the mutation rate (mu) has been difficult to measure directly, and increased cell turnover or selection could provide an alternative explanation. We recently developed an assay for mu using PIG-A as a sentinel gene and estimated that its average value is 10.6 x 10(-7) mutations per cell division in B-lymphoblastoid cell lines (BLCLs) from normal donors. Here we have measured mu in human malignancies and found that it was elevated in cell lines derived from T cell acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma in transformed phase, and 2 plasma cell neoplasms. In contrast, mu was much lower in a marginal zone lymphoma cell line and 5 other plasma cell neoplasms. The highest mu value that we measured, 3286 x 10(-7), is 2 orders of magnitude above the range we have observed in non-malignant human cells. We conclude that the type of genomic instability detected in this assay is a common but not universal feature of hematologic malignancies.
有人提出，高突变率是解释癌症中突变高频的必要条件。然而，从历史上看，突变率（mu）很难直接测量，细胞周转率增加或选择可能提供了另一种解释。我们最近开发了一种使用 PIG-A 作为哨兵基因的 mu 测定法，估计其在来自正常供体的 B 淋巴细胞白血病细胞系（BLCL）中的平均每个细胞分裂为 10.6×10（-7）个突变。在这里，我们测量了人类恶性肿瘤中的 mu，发现它在源自 T 细胞急性淋巴细胞白血病、套细胞淋巴瘤、转化期滤泡性淋巴瘤和 2 种浆细胞瘤系的细胞中升高。相比之下，在边缘区淋巴瘤细胞系和其他 5 种浆细胞瘤系中，mu 要低得多。我们测量的最高 mu 值为 3286×10（-7），比我们在非恶性人类细胞中观察到的范围高出 2 个数量级。我们得出结论，该测定法中检测到的基因组不稳定性类型是血液系统恶性肿瘤的常见而非普遍特征。
