Fanconi anemia (FA) is a genetic disorder characterized by congenital anomalies, bone marrow failure, and cancer predisposition. Among other solid cancers, head and neck squamous cell carcinoma (FA HNSCC) is the most common cancer type in individuals with FA. The FA pathway is required for the complete repair of DNA interstrand crosslinks (ICLs), and unresolved ICLs result in cell cycle arrest, apoptosis, or complex chromosomal rearrangements due to chromosome breaks, ultimately leading to tumorigenesis. FA HNSCCs present earlier (median age of onset in the 30s) and exhibit a more aggressive course with frequent recurrence and second primaries, and entail a poorer survival rate compared to sporadic HNSCC. FA HNSCCs are mostly human papillomavirus (HPV)-negative and frequently carry somatic copy number variations (CNVs), which amplify oncogenes implicated in sporadic HNSCC, but single-nucleotide variants or small insertions and deletions are less frequent than in HPV-negative sporadic HNSCC. A subset of sporadic HNSCC carries pathogenic mutations or promoter methylation in FA genes, which also harbor characteristic somatic CNVs, suggesting shared molecular underpinnings with FA HNSCC. Heightened inflammation from genomic instability and transcriptional activation of retrotransposons contribute to tumorigenesis and increased invasiveness by the epithelial-to-mesenchymal transition. Due to heightened sensitivity to DNA crosslinking agents in patients with FA, platinum-based chemotherapy is generally avoided, which presents a significant hurdle for treatment and thereby leaves limited therapeutic options. Surgical management is the mainstay of therapy if possible, and targeted therapy has been increasingly studied in HNSCC in FA.
范可尼贫血是一种以先天性异常、骨髓衰竭和癌症易感性为特征的遗传性疾病。在各类实体肿瘤中，头颈部鳞状细胞癌是范可尼贫血患者最常见的癌症类型。范可尼贫血通路是DNA链间交联完全修复所必需的，未修复的链间交联会导致细胞周期停滞、凋亡或染色体断裂引发的复杂染色体重排，最终导致肿瘤发生。与散发性头颈鳞癌相比，范可尼贫血相关头颈鳞癌发病更早（中位发病年龄约30岁），病程更具侵袭性，常出现复发和第二原发癌，且生存率更低。此类肿瘤大多为人乳头瘤病毒阴性，常携带体细胞拷贝数变异——这些变异会扩增散发性头颈鳞癌相关的致癌基因，但其单核苷酸变异或小片段插入缺失的发生频率低于HPV阴性散发性头颈鳞癌。部分散发性头颈鳞癌携带范可尼贫血基因的致病性突变或启动子甲基化，同时存在特征性体细胞拷贝数变异，提示其与范可尼贫血相关头颈鳞癌具有共同的分子基础。基因组不稳定性引发的炎症加剧以及逆转录转座子的转录激活，通过上皮-间质转化促进肿瘤发生并增强侵袭性。由于范可尼贫血患者对DNA交联剂敏感性增高，通常需避免使用铂类化疗药物，这给治疗带来重大障碍，导致治疗方案有限。在可行的情况下，手术切除是主要治疗手段，而靶向治疗在范可尼贫血相关头颈鳞癌中的研究日益增多。
肿瘤(癌症)患者之家