Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer.

Szczegóły
Abstrakt

Tytuł:: Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer.
Autorzy:: Kocakavuk E; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.; DKFZ Division of Translational Neurooncology at the West German Cancer Center, German Cancer Consortium Partner Site, University Hospital Essen, Essen, Germany.; Department of Neurosurgery, University Hospital Essen, Essen, Germany.
Anderson KJ; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Varn FS; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Johnson KC; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Amin SB; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Sulman EP; NYU Langone Health, New York, NY, USA.
Lolkema MP; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Barthel FP; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. .; Department of Pathology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. .; Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, USA. .
Verhaak RGW; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. .
Źródło:: Nature genetics [Nat Genet] 2021 Jul; Vol. 53 (7), pp. 1088-1096. Date of Electronic Publication: 2021 May 27.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Original Publication: New York, NY : Nature Pub. Co., c1992-
MeSH Terms:: Neoplasms/*genetics
Neoplasms/*mortality
Radiotherapy/*adverse effects
Sequence Deletion/*radiation effects
DNA Damage/radiation effects ; Humans ; Mutagenesis/radiation effects ; Neoplasm Recurrence, Local ; Neoplasms/epidemiology ; Neoplasms/radiotherapy ; Prognosis ; Radiation, Ionizing
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Grant Information:: R01 CA190121 United States CA NCI NIH HHS; R21 NS114873 United States NS NINDS NIH HHS; P30 CA034196 United States CA NCI NIH HHS; K99 CA226387 United States CA NCI NIH HHS; R01 CA237208 United States CA NCI NIH HHS; R01 CA255705 United States CA NCI NIH HHS
Entry Date(s):: Date Created: 20210528 Date Completed: 20210830 Latest Revision: 20230202
Update Code:: 20240105
PubMed Central ID:: PMC8483261
DOI:: 10.1038/s41588-021-00874-3
PMID:: 34045764
: Czasopismo naukowe

Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant increases in the burden of small deletions (5-15 bp) and large deletions (20+ bp to chromosome-arm length). Small deletions were characterized by a larger span size, lacking breakpoint microhomology and were genomically more dispersed when compared to pre-existing deletions and deletions in non-irradiated tumors. Mutational signature analysis implicated classical non-homologous end-joining-mediated DNA damage repair and APOBEC mutagenesis following radiotherapy. A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival. These results may be leveraged to predict sensitivity to radiation therapy in recurrent cancer.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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