دورية أكاديمية
PL03.2.A Radiotherapy is associated with a deletion signature that contributes to poor outcomes in glioma patients
| العنوان: | PL03.2.A Radiotherapy is associated with a deletion signature that contributes to poor outcomes in glioma patients |
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| المؤلفون: | Kocakavuk, E, Anderson, K J, Varn, F S, Johnson, K C, Amin, S B, Sulman, E P, Lolkema, M P, Barthel, F P, Verhaak, R G W |
| المصدر: | Neuro-Oncology ; volume 23, issue Supplement_2, page ii2-ii2 ; ISSN 1522-8517 1523-5866 |
| بيانات النشر: | Oxford University Press (OUP) |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Neurology (clinical), Oncology |
| الوصف: | BACKGROUND Diffuse gliomas are highly aggressive brain tumors that invariably relapse despite treatment with chemo- and radiotherapy. Treatment with alkylating chemotherapy can drive tumors to develop a hypermutator phenotype. In contrast, the genomic effects of radiation therapy (RT) remain largely unknown. MATERIAL AND METHODS We analyzed the mutational spectra following treatment with RT in whole genome or exome sequencing data from 190 paired primary-recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 3693 post-treatment metastatic tumors from the Hartwig Medical Foundation (HMF). RESULTS We identified a significant increase in the burden of small deletions following radiation therapy that was independent of other factors (P = 3e-03, multivariable log-linear regression). These novel deletions demonstrated distinct characteristics when compared to pre-existing deletions present prior to RT-treatment and deletions in RT-untreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and HMF, P = 1.5e-04 and P = 6e-16, respectively; Mann-Whitney U test), an increased distance to repetitive DNA elements (P < 2.2e-16, Kolmogorov-Smirnov test) and a lack of microhomology at breakpoints (P = 6.6e-05, paired Wilcoxon signed-rank test). Furthermore, mutational signature analysis confirmed the distinct genomic characteristics of RT-associated deletions when compared to deletions arising via homologous recombination deficiency or microsatellite instability. These observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double strand break repair of RT-induced DNA damage. Furthermore, RT resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions in IDHmut glioma (P= 1.9e-05, Fisher’s exact test). Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and HMF, P = 3.4e-02 and P < ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1093/neuonc/noab180.004 |
| الإتاحة: | https://doi.org/10.1093/neuonc/noab180.004Test http://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_2/ii2/40329604/noab180.004.pdfTest |
| حقوق: | https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_modelTest |
| رقم الانضمام: | edsbas.95A4CB2C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/neuonc/noab180.004 |
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