Abstract:
We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom\'s syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.
摘要:
我们探讨了与DNA双链断裂的反应和修复相关的基因缺陷使口腔潜在恶性疾病(OPMD)发生恶性转化为口腔鳞状细胞癌(OSCC)的可能性。同源重组/范可尼贫血(HR/FA)缺陷,但不是在非同源末端连接中,导致DNA修复途径似乎与易患OSCC的家族性疾病的特征一致(FA,布卢姆综合征,共济失调毛细血管扩张症);对于年轻患者中发生的OSCC,有时很少/没有暴露于经典风险因素。即使在先天性角化症中,端粒酶复合物的一种疾病,也容易患OSCC,维持端粒长度的尝试涉及具有共享HR基因的通路。因此,HR/FA途径中的缺陷在倾向于OSCC的条件下似乎是关键的。还有一些证据表明,HR/FA通路的异常与散发性病例OPMD和OSCC的恶性转化有关。我们提供的数据显示,与一系列OPMD衍生的永生角质形成细胞系相比,HR/FA基因以细胞周期依赖性方式过表达。这项研究的观察结果强烈支持HA/FADNA修复途径在OSCC发展中的重要作用。