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Genomic signature of Fanconi anemia DNA repair pathway deficiency in cancer

ABSTRACT: Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage. The FA repair pathway protects against carcinogenic endogenous and exogenous aldehydes. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (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 human papillomavirus (HPV) infection. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of high numbers of structural variants (SVs). SVs 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 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 signaling, which would contribute to the aggressive nature of FA SCCs. We propose that genomic instability in sporadic HPV-negative HNSCC may arise consequent to the FA repair pathway being overwhelmed by ICL damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA crosslinking damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE195811 | GEO | 2022/09/04

REPOSITORIES: GEO

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