Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Department of Otolaryngology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mutat Res. 2013 Mar-Apr;743-744:78-88. doi: 10.1016/j.mrfmmm.2013.01.001. Epub 2013 Jan 17.
Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today's bone marrow failure treatments on tomorrow's solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility.
范可尼贫血症（FA）是一种罕见的遗传性隐性疾病，由已知编码 FA 途径成分的十五个基因之一的突变引起。在应对 DNA 损伤时，核 FA 蛋白通过一系列翻译后修饰和物理相互作用形成高分子量复合物，随后修复受损的 DNA。造血细胞对这些相互作用的丧失特别敏感，FA 患者几乎普遍发生骨髓衰竭。FA 作为一种疾病还具有癌症易感性的特点，这突出了 FA 途径在肿瘤抑制中的重要性，也将是本综述的重点。急性髓系白血病是最常见的癌症类型，通常继发于骨髓衰竭。然而，FA 患者也面临着头颈部和妇科生殖道鳞状细胞癌（SCC）的极高风险，在接受骨髓移植并从血液疾病中康复的个体中发病率更高。FA 在造血细胞与上皮细胞中的肿瘤抑制作用在机制上可能相似或不同。目前，确定特定于细胞区室的 FA 活性对于评估当今骨髓衰竭治疗对未来实体瘤发展的影响至关重要。我们希望目前的治疗方法能够得到优化，以降低造血细胞和上皮细胞恶性转化的风险。在这里，我们回顾了我们目前对 FA 途径作为应激反应、DNA 修复和鳞状细胞癌易感性的作用机制的理解。
