Harada K, Nishizaki T, Ozaki S, Kubota H, Ito H, Sasaki K
Department of Neurosurgery, Yamaguchi University School of Medicine, Japan.
Cancer Res. 1998 Oct 15;58(20):4694-700.
Although it is well-known that cancers show intratumoral phenotypic heterogeneity, genotypic studies have been scarce. Using comparative genomic hybridization and laser scanning cytometric analyses, we investigated intratumoral cytogenetic heterogeneity in 21 surgically removed gliomas including 11 glioblastomas (GBMs), 8 anaplastic astrocytomas (AAs) and 2 low-grade astrocytomas. Comparative genomic hybridization analysis revealed gain or amplification of 7p in 63%, gain of 7q in 73%, loss of 9p in 53%, loss of 10p in 47%, loss of 10q in 47%, loss of 13q in 53%, and loss of 22q in 37% of high-grade astrocytomas. Because these aberrations were region-independent within the same tumor, they did not contribute to intratumoral cytogenetic heterogeneity. Such heterogeneity was due to cytogenetic changes other than the above region-independent aberrations. Intratumoral cytogenetic heterogeneity was detected in 8 of 11 GBMs, 4 of 8 AAs, and none of the 2 low-grade astrocytomas. These observations suggest that cytogenetic changes at chromosomes 7, 9p, 10, 13, and 22 are primary events in high-grade astrocytomas and that subsequent cytogenetic changes involving increases in copy number provide intratumoral heterogeneity. DNA aneuploidy was detected by laser scanning cytometry in 5 of 11 GBMs and 1 of 8 AAs. All tumors with DNA aneuploidy exhibited intratumoral cytogenetic heterogeneity, and there was a significant correlation between DNA aneuploidy and intratumoral cytogenetic heterogeneity. These results support the notion that cytogenetic heterogeneity results from genetic instability within a tumor.
虽然众所周知癌症存在肿瘤内表型异质性，但基因分型研究却很匮乏。我们运用比较基因组杂交和激光扫描细胞计量分析方法，对21例手术切除的神经胶质瘤进行了肿瘤内细胞遗传学异质性研究，其中包括11例胶质母细胞瘤（GBM）、8例间变性星形细胞瘤（AA）和2例低级别星形细胞瘤。比较基因组杂交分析显示，在高级别星形细胞瘤中，63%出现7p增益或扩增，73%出现7q增益，53%出现9p缺失，47%出现10p缺失，47%出现10q缺失，53%出现13q缺失，37%出现22q缺失。由于这些畸变在同一肿瘤内与区域无关，它们并未导致肿瘤内细胞遗传学异质性。这种异质性是由上述与区域无关的畸变以外的细胞遗传学变化引起的。在11例GBM中有8例、8例AA中有4例检测到肿瘤内细胞遗传学异质性，而2例低级别星形细胞瘤均未检测到。这些观察结果表明，7号染色体、9p、10号、13号和22号染色体的细胞遗传学变化是高级别星形细胞瘤的主要事件，随后涉及拷贝数增加的细胞遗传学变化导致了肿瘤内异质性。通过激光扫描细胞计量术在11例GBM中的5例和8例AA中的1例检测到DNA非整倍体。所有存在DNA非整倍体的肿瘤均表现出肿瘤内细胞遗传学异质性，并且DNA非整倍体与肿瘤内细胞遗传学异质性之间存在显著相关性。这些结果支持了细胞遗传学异质性源于肿瘤内基因不稳定这一观点。
