Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage^1,2,3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes^4,5,6,7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas⁸ (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus⁹ (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

范可尼贫血 (FA) 是一种基因组不稳定的模型综合征，是由 DNA 链间交联修复缺陷导致染色体断裂^1,2,3引起的。FA 修复途径可防止内源性和外源性致癌醛^4,5,6,7。^{患有 FA 的人患头颈部 (HNSCC)、食管和肛门生殖器鳞状细胞癌8} (SCC)的可能性要高出数百到数千倍。FA 患者 SCC（FA SCC）的分子研究有限，目前尚不清楚 FA SCC 与主要由烟草和酒精暴露或人乳头瘤病毒 9 感染驱动的散发性 HNSCC 有何^关系（人乳头状瘤病毒）。在这里，通过对 FA SCC 的基因组和外显子组进行测序，我们证明了 FA 修复缺陷的主要基因组特征是存在大量结构变异。结构变异因小缺失、不平衡易位和折叠倒位而丰富，并且通常相互连接，从而形成复杂的重排。它们出现在TP53的背景下损失，但不是在 HPV 感染的情况下，并导致 HNSCC 驱动基因的体细胞拷贝数改变。我们进一步表明，FA 通路缺陷可能导致上皮-间充质转化和增强的角质形成细胞内在炎症信号传导，这将导致 FA SCC 的侵袭性。我们提出，散发性 HPV 阴性 HNSCC 的基因组不稳定性可能是由于 FA 修复途径被酒精和烟草衍生的醛引起的 DNA 链间交联损伤所淹没，使 FA SCC 成为研究 DNA 引起的肿瘤发生的有力模型-交联损伤。