Goossens-Beumer Inès J, Benard Anne, van Hoesel Anneke Q, Zeestraten Eliane C M, Putter Hein, Böhringer Stefan, Liefers Gerrit-Jan, Morreau Hans, van de Velde Cornelis J H, Kuppen Peter J K
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
Transl Res. 2015 May;165(5):578-88. doi: 10.1016/j.trsl.2014.11.001. Epub 2014 Nov 13.
Aging is one of the prime risk factors for the development of cancer. Expression patterns of epigenetic regulators, including histone modification levels, are altered during aging of normal cells, a phenomenon referred to as epigenetic drift. Furthermore, it is known that epigenetic mechanisms are involved in the development of cancer. We hypothesized that expression of histone modifications, acetylation of histone 3 lysine 9 (H3K9Ac) and trimethylation of histone 3 lysine 27 (H3K27me3), with reported normal age-related expression patterns might show an age-dependent prognostic value in colorectal cancer (CRC). To quantify expression, we performed immunohistochemical staining of these histone modifications on a tissue microarray containing colorectal tissues of the 254 patients with TNM stage I-III CRC. Stratification of patients according to survival status revealed age-related tumor expression patterns of both H3K9Ac and H3K27me3. Decreased expression with advancing age was observed in patients who were alive after follow-up (no-event group), whereas increased expression with advancing age was observed in patients who presented with a recurrence or death in follow-up (event group). These opposite expression patterns translated into an age-dependent prognostic value in CRC for the individual histone modifications and their combination. The prognostic value reverses with advancing age, high nuclear expression associated with good clinical outcome in young adults, and, in contrast, with worse clinical outcome in elderly patients. In conclusion, for the first time, we demonstrated prognostic impact of epigenetic biomarkers that reverses with advancing age. This new insight supports the hypothesis that CRC biology is different in young vs elderly patients and emphasizes the importance of focusing on age-related effects in CRC.
衰老 是癌症发生的主要风险因素之一。在正常细胞衰老过程中，包括组蛋白修饰水平在内的表观遗传调节因子的表达模式会发生改变，这种现象被称为表观遗传漂变。此外，已知表观遗传机制参与癌症的发生。我们假设，具有报道的正常年龄相关表达模式的组蛋白修饰，即组蛋白3赖氨酸9乙酰化（H3K9Ac）和组蛋白3赖氨酸27三甲基化（H3K3K27me3）的表达，可能在结直肠癌（CRC）中显示出年龄依赖性的预后价值。为了量化表达，我们在包含254例TNM I-III期CRC结直肠组织的组织芯片上对这些组蛋白修饰进行了免疫组织化学染色。根据生存状态对患者进行分层，揭示了H3K9Ac和H3K27me3与年龄相关的肿瘤表达模式。在随访后存活的患者（无事件组）中观察到随着年龄增长表达降低，而在随访中出现复发或死亡的患者（事件组）中观察到随着年龄增长表达增加。这些相反的表达模式转化为CRC中个体组蛋白修饰及其组合的年龄依赖性预后价值。预后价值随着年龄增长而逆转，高核表达在年轻成年人中与良好的临床结果相关，相反，在老年患者中与较差的临床结果相关。总之，我们首次证明了表观遗传生物标志物的预后影响随着年龄增长而逆转。这一新见解支持了CRC生物学在年轻患者和老年患者中不同的假设，并强调了关注CRC中年龄相关效应的重要性。
