Seng T J, Currey N, Cooper W A, Lee C-S, Chan C, Horvath L, Sutherland R L, Kennedy C, McCaughan B, Kohonen-Corish M R J
Cancer Research Program, Garvan Institute of Medical Research, Sydney 2010, Australia.
Br J Cancer. 2008 Jul 22;99(2):375-82. doi: 10.1038/sj.bjc.6604452. Epub 2008 Jul 1.
The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARbeta in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARbeta. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers.
目前对肺癌中3号染色体p臂基因改变的意义了解甚少。本研究旨在调查239例非小细胞肺癌（NSCLC）中肺癌和食管癌缺失基因1（DLEC1）、错配修复蛋白1（MLH1）及其他3p基因的启动子甲基化情况。在肿瘤中，DLEC1甲基化率为38.7%，MLH1为35.7%，视黄酸受体β（RARbeta）为51.7%，RAS相关结构域家族1A（RASSF1A）为32.4%，B淋巴瘤/白血病-2相关X蛋白（BLU）为35.3%。除RARbeta外，任意两种基因改变之间均存在关联。DLEC1甲基化是整个队列（P=0.025）和鳞状细胞癌（P=0.041）患者生存预后不良的独立标志物。MLH1甲基化也具有预后意义，尤其在大细胞癌中（P=0.006）。DLEC1/MLH1的一致性甲基化是整个队列中预后不良最强的独立指标（P=0.009）。然而，微卫星不稳定性和MLH1表达缺失很少见，这表明MLH1启动子甲基化在肺癌中通常不会导致基因沉默。这是第一项描述DLEC1和MLH1甲基化在NSCLC中预后价值的研究。一致性甲基化可能是3号染色体p臂该区域远距离表观遗传效应的结果，这种效应最近在其他癌症中也有描述。
