Title |
Structure and evolution of double minutes in diagnosis and relapse brain tumors
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Published in |
Acta Neuropathologica, September 2018
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DOI | 10.1007/s00401-018-1912-1 |
Pubmed ID | |
Authors |
Ke Xu, Liang Ding, Ti-Cheng Chang, Ying Shao, Jason Chiang, Heather Mulder, Shuoguo Wang, Tim I. Shaw, Ji Wen, Laura Hover, Clay McLeod, Yong-Dong Wang, John Easton, Michael Rusch, James Dalton, James R. Downing, David W. Ellison, Jinghui Zhang, Suzanne J. Baker, Gang Wu |
Abstract |
Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants. |
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Geographical breakdown
Country | Count | As % |
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United States | 6 | 50% |
Germany | 1 | 8% |
United Kingdom | 1 | 8% |
Portugal | 1 | 8% |
Spain | 1 | 8% |
Unknown | 2 | 17% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 6 | 50% |
Scientists | 5 | 42% |
Practitioners (doctors, other healthcare professionals) | 1 | 8% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 89 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 12 | 13% |
Student > Bachelor | 11 | 12% |
Student > Master | 9 | 10% |
Researcher | 9 | 10% |
Student > Doctoral Student | 8 | 9% |
Other | 12 | 13% |
Unknown | 28 | 31% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 30 | 34% |
Agricultural and Biological Sciences | 7 | 8% |
Medicine and Dentistry | 7 | 8% |
Computer Science | 3 | 3% |
Psychology | 3 | 3% |
Other | 13 | 15% |
Unknown | 26 | 29% |