组蛋白修饰的结肠癌临床预后价值与年龄的相关性研究

Age-dependent clinical prognostic value of histone modifications in colorectal cancer

摘要:

目的  评价组蛋白修饰在TNM Ⅰ~Ⅲ期结肠癌患者肿瘤细胞中的表达及其预后价值，并进一步探讨组蛋白修饰表达预后价值与年龄的相关性。方法  采用免疫组织化学方法检测254例TNM Ⅰ~Ⅲ期CRC患者组织芯片中组蛋白修饰表达情况。根据生存状态对患者进行分组，比较各组间组蛋白修饰形态H3K9ac和H3K27me3表达差异及其与年龄的相关性。结果  随着年龄增长，组蛋白修饰在随访期间存活患者中表达降低，而随着年龄增长，组蛋白修饰在随访期间复发或死亡患者中表达增加。组蛋白修饰在两组间的表达差异表明组蛋白修饰在结肠癌中的预后价值与年龄相关。组蛋白修饰细胞核高表达在年龄更低组中提示较好的临床结局，而在年龄更高组中提示更差的临床结局。结论  组蛋白修饰物H3K9ac和H3K27me3在细胞核中单独或联合高表达对结肠癌患者具有预后价值。随着年龄增加表观遗传标志物的预后影响不但发生变化，甚至发生逆转。年青和年老结肠癌患者的生物学存在差异，年龄对结肠癌具有重要影响。

Abstract:

Objective To assess the expression of histone modifications in tumor cells of the patients with TNM stage I-III colorectal cancer (CRC) and its clinical outcome and association with age at surgery. Methods To quantify expression, immunohistochemical staining of the histone modifications was performed on a tissue microarray containing colorectal tissues of the 254 patients with TNM stage I-III CRC. The patients were stratified according to survival status and age-related tumor expression patterns of both H3K9ac and H3K27me3 were compared. Results Decreased expression with advancing age was observed in the patients who were alive after follow-up (no-event group), whereas increased expression with advancing age was observed in the patients who presented with a recurrence or death during follow-up (event group). These opposite expression patterns translated into age-dependent prognostic value of the individual histone modifications and their combination in CRC. The prognostic value reversed with increasing age, high nuclear expression associated with good clinical outcome in the young adults, in contrast, with poor clinical outcome in the elderly patients. Conclusions We identified an age-dependent prognostic effect of nuclear expressions of histone modifications H3K9ac and H3K27me3 and their combination in patients with CRC. We have demonstrated for the first time the prognostic impact of an epigenetic marker can not only change but also reverse with increasing age. This observation supports the hypothesis that CRC biology is distinct between young adults and the elderly and emphasizes the importance of focusing on age-related effects in CRC.