Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

TitleGenomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsWebster ALH, Sanders MA, Patel K, Dietrich R, Noonan RJ, Lach FP, White RR, Goldfarb A, Hadi K, Edwards MM, Donovan FX, Hoogenboezem RM, Jung M, Sridhar S, Wiley TF, Fedrigo O, Tian H, Rosiene J, Heineman T, Kennedy JA, Bean L, Rosti RO, Tryon R, Gonzalez A-M, Rosenberg A, Luo J-D, Carroll TS, Shroff S, Beaumont M, Velleuer E, Rastatter JC, Wells SI, Surrall├ęs J, Bagby G, MacMillan ML, Wagner JE, Cancio M, Boulad F, Scognamiglio T, Vaughan R, Beaumont KG, Koren A, Imielinski M, Chandrasekharappa SC, Auerbach AD, Singh B, Kutler DI, Campbell PJ, Smogorzewska A
JournalNature
Volume612
Issue7940
Pagination495-502
Date Published2022 Dec
ISSN1476-4687
KeywordsAldehydes, DNA Damage, DNA Repair, Fanconi Anemia, Genomics, Head and Neck Neoplasms, Humans, Papillomavirus Infections, Squamous Cell Carcinoma of Head and Neck
Abstract

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. 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.

DOI10.1038/s41586-022-05253-4
Alternate JournalNature
PubMed ID36450981
PubMed Central IDPMC10202100
Grant ListR01 HL120922 / HL / NHLBI NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA204127 / CA / NCI NIH HHS / United States
DP2 GM123495 / GM / NIGMS NIH HHS / United States
Related Faculty: 
Theresa Scognamiglio, M.D.

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