AI Article Synopsis

  • - Fanconi anaemia (FA) is a genetic condition that makes DNA repair faulty, leading to chromosome breakage and a significantly higher risk of specific cancers such as head and neck, esophageal, and anogenital squamous cell carcinomas compared to the general population.
  • - Research reveals that squamous cell carcinomas from FA patients exhibit numerous structural variants, which include small deletions and complex rearrangements, often occurring alongside loss of the TP53 gene but not related to HPV infections.
  • - The instability caused by FA may trigger processes like epithelial-to-mesenchymal transition and heightened inflammatory signaling in skin cells, highlighting the potential for FA's unique genomic issues to inform understanding of sporadic HNSCC linked to tobacco and alcohol

Article Abstract

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal 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 infection with human papillomavirus (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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202100PMC
http://dx.doi.org/10.1038/s41586-022-05253-4DOI Listing

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