Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer

Andrew L. H. Webster, Mathijs A. Sanders, Krupa Patel, Ralf Dietrich, Raymond J. Noonan, Francis P. Lach, Ryan R. White, Audrey Goldfarb, Kevin Hadi, Matthew M. Edwards, Frank X. Donovan, Remco M. Hoogenboezem, Moonjung Jung, Sunandini Sridhar, Tom F. Wiley, Olivier Fedrigo, Huasong Tian, Joel Rosiene, Thomas Heineman, Jennifer A. Kennedy, Lorenzo Bean, Rasim O. Rosti, Rebecca Tryon, Ashlyn-Maree Gonzalez, Allana Rosenberg, Ji-Dung Luo, Thomas S. Carroll, Sanjana Shroff, Michael Beaumont, Eunike Velleuer, Jeff C. Rastatter, Susanne I. Wells, Jordi Surrallés, Grover Bagby, Margaret L. MacMillan, John E. Wagner, Maria Cancio, Farid Boulad, Theresa Scognamiglio, Roger Vaughan, Kristin G. Beaumont, Amnon Koren, Marcin Imielinski, Settara C. Chandrasekharappa, Arleen D. Auerbach, Bhuvanesh Singh, David I. Kutler, Peter J. Campbell and Agata Smogorzewska ()
Additional contact information
Andrew L. H. Webster: Rockefeller University
Mathijs A. Sanders: Wellcome Sanger Institute
Krupa Patel: Rockefeller University
Ralf Dietrich: Deutsche Fanconi-Anämie-Hilfe e.V
Raymond J. Noonan: Rockefeller University
Francis P. Lach: Rockefeller University
Ryan R. White: Rockefeller University
Audrey Goldfarb: Rockefeller University
Kevin Hadi: Weill Cornell Medicine and New York Genome Center
Matthew M. Edwards: Cornell University
Frank X. Donovan: National Institutes of Health
Remco M. Hoogenboezem: Erasmus MC Cancer Institute
Moonjung Jung: Rockefeller University
Sunandini Sridhar: Rockefeller University
Tom F. Wiley: Rockefeller University
Olivier Fedrigo: Rockefeller University
Huasong Tian: Weill Cornell Medicine and New York Genome Center
Joel Rosiene: Weill Cornell Medicine and New York Genome Center
Thomas Heineman: Rockefeller University
Jennifer A. Kennedy: Rockefeller University
Lorenzo Bean: Rockefeller University
Rasim O. Rosti: Rockefeller University
Rebecca Tryon: University of Minnesota
Ashlyn-Maree Gonzalez: Rockefeller University
Allana Rosenberg: Rockefeller University
Ji-Dung Luo: Rockefeller University
Thomas S. Carroll: Rockefeller University
Sanjana Shroff: Department of Genetics and Genomic Sciences. Icahn School of Medicine, Mount Sinai
Michael Beaumont: Department of Genetics and Genomic Sciences. Icahn School of Medicine, Mount Sinai
Eunike Velleuer: University Hospital of Düsseldorf
Jeff C. Rastatter: Northwestern University
Susanne I. Wells: University of Cincinnati College of Medicine
Jordi Surrallés: Institut de Recerca Hospital de la Santa Creu i Sant Pau–IIB Sant Pau
Grover Bagby: Oregon Health and Science University
Margaret L. MacMillan: University of Minnesota
John E. Wagner: University of Minnesota
Maria Cancio: Memorial Sloan Kettering Cancer Center
Farid Boulad: Memorial Sloan Kettering Cancer Center
Theresa Scognamiglio: Weill Cornell Medicine
Roger Vaughan: The Rockefeller University
Kristin G. Beaumont: Department of Genetics and Genomic Sciences. Icahn School of Medicine, Mount Sinai
Amnon Koren: Cornell University
Marcin Imielinski: Weill Cornell Medicine and New York Genome Center
Settara C. Chandrasekharappa: National Institutes of Health
Arleen D. Auerbach: The Rockefeller University
Bhuvanesh Singh: Memorial Sloan Kettering Cancer Center
David I. Kutler: Weill Cornell Medical College
Peter J. Campbell: Wellcome Sanger Institute
Agata Smogorzewska: Rockefeller University

Nature, 2022, vol. 612, issue 7940, 495-502

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05253-4

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