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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 495-502 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 612 |
| Issue number | 7940 |
| DOIs | |
| State | Published - Dec 15 2022 |
Bibliographical note
Funding Information:We thank the participants and their families who donated their tissues to IFAR; the physicians who provided research samples and clinical information; the staff of Fanconi Anemia Research Fund, especially S. Planck for referrals to IFAR; National Disease Research Interchange (NDRI) for providing samples; M. Grompe for providing Fanca mutant mice; members of the Laboratory of Genome Maintenance for advice; N. Papazian and T. Cupedo for assistance with sample processing; E. Bindels for assistance with single-cell analysis; staff of the Genomic, Reference Genome, Bioinformatics and Flow Cytometry resource centres at the Rockefeller University for their expert advice and contribution; E. Fuchs and members of her laboratory for advice on keratinocyte growth conditions. Genomic data from non-FA SCCs are in part based on data generated by the TCGA Research Network (https://www.cancer.gov/tcga ). This study was supported by the Pershing Square Sohn Prize for Young Investigators in Cancer Research (A.S.), Fanconi Anemia Research Fund (R.D., E.V. and A.S.), V Foundation grant T2019-013 (A.S.), National Institutes of Health (NIH) National Heart Lung and Blood Institute (R01 HL120922) (A.S.), National Cancer Institute (R01 CA204127) (A.S.), National Center for Advancing Translational Sciences (UL1 TR001866) (R.V. and A.S.), NIH award 1DP2-GM123495 (A.K.). S.C.C. acknowledges support from the Intramural Research Program of the NIH National Human Genome Research Institute. M.A.S. is supported by a Rubicon fellowship from NWO (019.153LW.038) and a KWF Kankerbestrijding Young Investigator Grant (12797/2019-2, Bas Mulder Award; Dutch Cancer Foundation). A.S. is a Howard Hughes Faculty Scholar.
Funding Information:
We thank the participants and their families who donated their tissues to IFAR; the physicians who provided research samples and clinical information; the staff of Fanconi Anemia Research Fund, especially S. Planck for referrals to IFAR; National Disease Research Interchange (NDRI) for providing samples; M. Grompe for providing Fanca mutant mice; members of the Laboratory of Genome Maintenance for advice; N. Papazian and T. Cupedo for assistance with sample processing; E. Bindels for assistance with single-cell analysis; staff of the Genomic, Reference Genome, Bioinformatics and Flow Cytometry resource centres at the Rockefeller University for their expert advice and contribution; E. Fuchs and members of her laboratory for advice on keratinocyte growth conditions. Genomic data from non-FA SCCs are in part based on data generated by the TCGA Research Network ( https://www.cancer.gov/tcga ). This study was supported by the Pershing Square Sohn Prize for Young Investigators in Cancer Research (A.S.), Fanconi Anemia Research Fund (R.D., E.V. and A.S.), V Foundation grant T2019-013 (A.S.), National Institutes of Health (NIH) National Heart Lung and Blood Institute (R01 HL120922) (A.S.), National Cancer Institute (R01 CA204127) (A.S.), National Center for Advancing Translational Sciences (UL1 TR001866) (R.V. and A.S.), NIH award 1DP2-GM123495 (A.K.). S.C.C. acknowledges support from the Intramural Research Program of the NIH National Human Genome Research Institute. M.A.S. is supported by a Rubicon fellowship from NWO (019.153LW.038) and a KWF Kankerbestrijding Young Investigator Grant (12797/2019-2, Bas Mulder Award; Dutch Cancer Foundation). A.S. is a Howard Hughes Faculty Scholar.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
