Brownhill S C, Taylor C, Burchill S A
Candlelighter's Children's Cancer Research Laboratory, St. James's University Hospital, Beckett Street, LS9 7TF Leeds, UK.
Br J Cancer. 2007 Jun 18;96(12):1914-23. doi: 10.1038/sj.bjc.6603819. Epub 2007 May 29.
Chromosome 9p21 gene copy number in Ewing's sarcoma family of tumour (ESFT) cell lines and primary ESFT has been evaluated using Multiplex Ligation-dependent probe amplification, and the clinical significance of CDKN2A loss and p16/p14(ARF) expression investigated. Homozygous deletion of CDKN2A was identified in 4/9 (44%) of ESFT cell lines and 4/42 (10%) primary ESFT; loss of one copy of CDKN2A was identified in a further 2/9 (22%) cell lines and 2/42 (5%) tumours. CDKN2B was co-deleted in three (33%) cell lines and two (5%) tumours. Co-deletion of the MTAP gene was observed in 1/9 (11%) cell lines and 3/42 (7%) tumours. No correlation was observed between CDKN2A deletion and clinical parameters. However, co-expression of high levels of p16/p14(ARF) mRNA predicted a poor event-free survival (P=0.046, log-rank test). High levels of p16/p14(ARF) mRNA did not correlate with high expression of p16 protein. Furthermore, p16 protein expression did not predict event-free or overall survival. Methylation is not a common mechanism of p16 gene silencing in ESFT. These studies demonstrate that loss (homozygous deletion or single copy) of CDKN2A was not prognostically significant in primary ESFT. However, high levels of p16/p14(ARF) mRNA expression were predictive of a poor event-free survival and should be investigated further.
利用多重连接依赖探针扩增技术评估了尤因肉瘤家族性肿瘤（ESFT）细胞系和原发性ESFT中9号染色体p21区域的基因拷贝数，并研究了CDKN2A缺失及p16/p14（ARF）表达的临床意义。在4/9（44%）的ESFT细胞系和4/42（10%）的原发性ESFT中鉴定出CDKN2A的纯合缺失；在另外2/9（22%）的细胞系和2/42（5%）的肿瘤中鉴定出CDKN2A单拷贝缺失。在3个（33%）细胞系和2个（5%）肿瘤中观察到CDKN2B的共同缺失。在1/9（11%）的细胞系和3/42（7%）的肿瘤中观察到MTAP基因的共同缺失。未观察到CDKN2A缺失与临床参数之间的相关性。然而，高水平p16/p14（ARF）mRNA的共表达预示无事件生存期较差（P = 0.046，对数秩检验）。高水平的p16/p14（ARF）mRNA与p16蛋白的高表达不相关。此外，p16蛋白表达不能预测无事件生存期或总生存期。甲基化不是ESFT中p16基因沉默的常见机制。这些研究表明，在原发性ESFT中，CDKN2A的缺失（纯合缺失或单拷贝缺失）在预后方面无显著意义。然而，高水平的p16/p14（ARF）mRNA表达可预测无事件生存期较差，应进一步研究。
