Al Kuraya Khawla, Siraj Abdul Khalid, Bavi Prashant, Al-Jomah Naif, El-Solh Hassan, Ezzat Adnan, Al-Dayel Fouad, Belgaumi Asim, Al-Kofide Amani, Sabbah Rajeh, Sheikh Salwa, Amr Samir, Simon Ronald, Sauter Guido
Cancer Genomics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
Mod Pathol. 2006 Aug;19(8):1124-9. doi: 10.1038/modpathol.3800631. Epub 2006 May 19.
Recent studies have suggested a potential prognostic role of alterations of the fragile histidine triad (FHIT) gene in diffuse large B-cell lymphoma. To evaluate possible mechanisms of FHIT inactivation and to further clarify its potential prognostic relevance, we analyzed a set of 114 diffuse large B-cell lymphoma with clinical follow-up information. Tissue microarrays were analyzed by immunohistochemistry for protein expression, and corresponding DNA samples were analyzed for FHIT promotor hypermethlyation. Reduced or absent FHIT expression was found in 75 of 114 diffuse large B-cell lymphoma (66%), but was unrelated to clinical tumor stage or patient prognosis. FHIT promotor hypermethylation was observed in 29 of 93 (23%) interpretable diffuse large B-cell lymphoma. Hypermethylation was not significantly correlated to protein expression loss, which could be explained by competing mechanisms for FHIT inactivation in a substantial fraction of non FHIT hypermethylated diffuse large B-cell lymphoma. Hypermethylation was significantly associated with poor prognosis of diffuse large B-cell lymphoma patients and predominantly seen in nongerminal center diffuse large B-cell lymphoma (27%), but less frequent (13%) in germinal center diffuse large B-cell lymphoma. In summary, these data suggest that promotor hypermethylation is responsible for reduced FHIT expression in a substantial subset of diffuse large B-cell lymphoma, which is primarily composed of nongerminal center subtype with poor patient prognosis.
近期研究表明，脆性组氨酸三联体（FHIT）基因改变在弥漫性大B细胞淋巴瘤中可能具有预后作用。为评估FHIT失活的可能机制，并进一步阐明其潜在的预后相关性，我们分析了一组114例具有临床随访信息的弥漫性大B细胞淋巴瘤。通过免疫组织化学分析组织微阵列以检测蛋白表达，并对相应的DNA样本分析FHIT启动子高甲基化情况。在114例弥漫性大B细胞淋巴瘤中，有75例（66%）发现FHIT表达降低或缺失，但这与临床肿瘤分期或患者预后无关。在93例可解释的弥漫性大B细胞淋巴瘤中，有29例（23%）观察到FHIT启动子高甲基化。高甲基化与蛋白表达缺失无显著相关性，这可以用相当一部分非FHIT高甲基化的弥漫性大B细胞淋巴瘤中FHIT失活的竞争机制来解释。高甲基化与弥漫性大B细胞淋巴瘤患者的不良预后显著相关，主要见于非生发中心弥漫性大B细胞淋巴瘤（27%），而生发中心弥漫性大B细胞淋巴瘤中频率较低（13%）。总之，这些数据表明，启动子高甲基化是弥漫性大B细胞淋巴瘤相当一部分亚组中FHIT表达降低的原因，该亚组主要由患者预后不良的非生发中心亚型组成。
