New Study Investigates Genomics of Fanconi Anemia Repair Pathway in Cancer

A study appearing in Nature reveals new insights into how the loss of a DNA repair pathway contributes to head and neck squamous cell carcinomas (HNSCCs). People with Fanconi anemia, a hereditary bone marrow failure disorder, are vastly more likely to develop HNSCC and other squamous cell carcinomas (SCCs). The condition is caused by a deficiency in DNA interstrand crosslink repair, which resulting in chromosome breakage, and the so-called FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes, though it is unclear how FA SCCs relate to sporadic HNSCCs such as those driven by tobacco and alcohol use or human papillomavirus (HPV) infection. In the new study, a group led by Rockefeller University researchers sequenced the genomes and/or exomes of 55 independent FA SCCs and three adenocarcinomas from 50 individuals. Through this, they found that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants that are enriched for small deletions, unbalanced translocations, and fold-back inversions and are often connected into complex rearrangements. These structural variants "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," the study's authors write. Based on these and their other findings, the investigators 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."