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Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(–) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this p...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291/ https://www.ncbi.nlm.nih.gov/pubmed/33535033 http://dx.doi.org/10.1016/j.celrep.2021.108707 |
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author | Carrot-Zhang, Jian Yao, Xiaotong Devarakonda, Siddhartha Deshpande, Aditya Damrauer, Jeffrey S. Silva, Tiago Chedraoui Wong, Christopher K. Choi, Hyo Young Felau, Ina Robertson, A. Gordon Castro, Mauro A.A. Bao, Lisui Rheinbay, Esther Liu, Eric Minwei Trieu, Tuan Haan, David Yau, Christina Hinoue, Toshinori Liu, Yuexin Shapira, Ofer Kumar, Kiran Mungall, Karen L. Zhang, Hailei Lee, Jake June-Koo Berger, Ashton Gao, Galen F. Zhitomirsky, Binyamin Liang, Wen-Wei Zhou, Meng Moorthi, Sitapriya Berger, Alice H. Collisson, Eric A. Zody, Michael C. Ding, Li Cherniack, Andrew D. Getz, Gad Elemento, Olivier Benz, Christopher C. Stuart, Josh Zenklusen, J.C. Beroukhim, Rameen Chang, Jason C. Campbell, Joshua D. Hayes, D. Neil Yang, Lixing Laird, Peter W. Weinstein, John N. Kwiatkowski, David J. Tsao, Ming S. Travis, William D. Khurana, Ekta Berman, Benjamin P. Hoadley, Katherine A. Robine, Nicolas Meyerson, Matthew Govindan, Ramaswamy Imielinski, Marcin |
author_facet | Carrot-Zhang, Jian Yao, Xiaotong Devarakonda, Siddhartha Deshpande, Aditya Damrauer, Jeffrey S. Silva, Tiago Chedraoui Wong, Christopher K. Choi, Hyo Young Felau, Ina Robertson, A. Gordon Castro, Mauro A.A. Bao, Lisui Rheinbay, Esther Liu, Eric Minwei Trieu, Tuan Haan, David Yau, Christina Hinoue, Toshinori Liu, Yuexin Shapira, Ofer Kumar, Kiran Mungall, Karen L. Zhang, Hailei Lee, Jake June-Koo Berger, Ashton Gao, Galen F. Zhitomirsky, Binyamin Liang, Wen-Wei Zhou, Meng Moorthi, Sitapriya Berger, Alice H. Collisson, Eric A. Zody, Michael C. Ding, Li Cherniack, Andrew D. Getz, Gad Elemento, Olivier Benz, Christopher C. Stuart, Josh Zenklusen, J.C. Beroukhim, Rameen Chang, Jason C. Campbell, Joshua D. Hayes, D. Neil Yang, Lixing Laird, Peter W. Weinstein, John N. Kwiatkowski, David J. Tsao, Ming S. Travis, William D. Khurana, Ekta Berman, Benjamin P. Hoadley, Katherine A. Robine, Nicolas Meyerson, Matthew Govindan, Ramaswamy Imielinski, Marcin |
author_sort | Carrot-Zhang, Jian |
collection | PubMed |
description | RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(–) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(–) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(–) cases are required to understand this important LUAD subset. |
format | Online Article Text |
id | pubmed-8009291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-80092912021-03-30 Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway Carrot-Zhang, Jian Yao, Xiaotong Devarakonda, Siddhartha Deshpande, Aditya Damrauer, Jeffrey S. Silva, Tiago Chedraoui Wong, Christopher K. Choi, Hyo Young Felau, Ina Robertson, A. Gordon Castro, Mauro A.A. Bao, Lisui Rheinbay, Esther Liu, Eric Minwei Trieu, Tuan Haan, David Yau, Christina Hinoue, Toshinori Liu, Yuexin Shapira, Ofer Kumar, Kiran Mungall, Karen L. Zhang, Hailei Lee, Jake June-Koo Berger, Ashton Gao, Galen F. Zhitomirsky, Binyamin Liang, Wen-Wei Zhou, Meng Moorthi, Sitapriya Berger, Alice H. Collisson, Eric A. Zody, Michael C. Ding, Li Cherniack, Andrew D. Getz, Gad Elemento, Olivier Benz, Christopher C. Stuart, Josh Zenklusen, J.C. Beroukhim, Rameen Chang, Jason C. Campbell, Joshua D. Hayes, D. Neil Yang, Lixing Laird, Peter W. Weinstein, John N. Kwiatkowski, David J. Tsao, Ming S. Travis, William D. Khurana, Ekta Berman, Benjamin P. Hoadley, Katherine A. Robine, Nicolas Meyerson, Matthew Govindan, Ramaswamy Imielinski, Marcin Cell Rep Article RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(–) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(–) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(–) cases are required to understand this important LUAD subset. 2021-02-02 /pmc/articles/PMC8009291/ /pubmed/33535033 http://dx.doi.org/10.1016/j.celrep.2021.108707 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Carrot-Zhang, Jian Yao, Xiaotong Devarakonda, Siddhartha Deshpande, Aditya Damrauer, Jeffrey S. Silva, Tiago Chedraoui Wong, Christopher K. Choi, Hyo Young Felau, Ina Robertson, A. Gordon Castro, Mauro A.A. Bao, Lisui Rheinbay, Esther Liu, Eric Minwei Trieu, Tuan Haan, David Yau, Christina Hinoue, Toshinori Liu, Yuexin Shapira, Ofer Kumar, Kiran Mungall, Karen L. Zhang, Hailei Lee, Jake June-Koo Berger, Ashton Gao, Galen F. Zhitomirsky, Binyamin Liang, Wen-Wei Zhou, Meng Moorthi, Sitapriya Berger, Alice H. Collisson, Eric A. Zody, Michael C. Ding, Li Cherniack, Andrew D. Getz, Gad Elemento, Olivier Benz, Christopher C. Stuart, Josh Zenklusen, J.C. Beroukhim, Rameen Chang, Jason C. Campbell, Joshua D. Hayes, D. Neil Yang, Lixing Laird, Peter W. Weinstein, John N. Kwiatkowski, David J. Tsao, Ming S. Travis, William D. Khurana, Ekta Berman, Benjamin P. Hoadley, Katherine A. Robine, Nicolas Meyerson, Matthew Govindan, Ramaswamy Imielinski, Marcin Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title | Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title_full | Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title_fullStr | Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title_full_unstemmed | Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title_short | Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway |
title_sort | whole-genome characterization of lung adenocarcinomas lacking alterations in the rtk/ras/raf pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291/ https://www.ncbi.nlm.nih.gov/pubmed/33535033 http://dx.doi.org/10.1016/j.celrep.2021.108707 |
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