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Common germline-somatic variant interactions in advanced urothelial cancer

The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifyi...

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Autores principales: Vosoughi, Aram, Zhang, Tuo, Shohdy, Kyrillus S., Vlachostergios, Panagiotis J., Wilkes, David C., Bhinder, Bhavneet, Tagawa, Scott T., Nanus, David M., Molina, Ana M., Beltran, Himisha, Sternberg, Cora N., Motanagh, Samaneh, Robinson, Brian D., Xiang, Jenny, Fan, Xiao, Chung, Wendy K., Rubin, Mark A., Elemento, Olivier, Sboner, Andrea, Mosquera, Juan Miguel, Faltas, Bishoy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713129/
https://www.ncbi.nlm.nih.gov/pubmed/33273457
http://dx.doi.org/10.1038/s41467-020-19971-8
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author Vosoughi, Aram
Zhang, Tuo
Shohdy, Kyrillus S.
Vlachostergios, Panagiotis J.
Wilkes, David C.
Bhinder, Bhavneet
Tagawa, Scott T.
Nanus, David M.
Molina, Ana M.
Beltran, Himisha
Sternberg, Cora N.
Motanagh, Samaneh
Robinson, Brian D.
Xiang, Jenny
Fan, Xiao
Chung, Wendy K.
Rubin, Mark A.
Elemento, Olivier
Sboner, Andrea
Mosquera, Juan Miguel
Faltas, Bishoy M.
author_facet Vosoughi, Aram
Zhang, Tuo
Shohdy, Kyrillus S.
Vlachostergios, Panagiotis J.
Wilkes, David C.
Bhinder, Bhavneet
Tagawa, Scott T.
Nanus, David M.
Molina, Ana M.
Beltran, Himisha
Sternberg, Cora N.
Motanagh, Samaneh
Robinson, Brian D.
Xiang, Jenny
Fan, Xiao
Chung, Wendy K.
Rubin, Mark A.
Elemento, Olivier
Sboner, Andrea
Mosquera, Juan Miguel
Faltas, Bishoy M.
author_sort Vosoughi, Aram
collection PubMed
description The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.
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spelling pubmed-77131292020-12-07 Common germline-somatic variant interactions in advanced urothelial cancer Vosoughi, Aram Zhang, Tuo Shohdy, Kyrillus S. Vlachostergios, Panagiotis J. Wilkes, David C. Bhinder, Bhavneet Tagawa, Scott T. Nanus, David M. Molina, Ana M. Beltran, Himisha Sternberg, Cora N. Motanagh, Samaneh Robinson, Brian D. Xiang, Jenny Fan, Xiao Chung, Wendy K. Rubin, Mark A. Elemento, Olivier Sboner, Andrea Mosquera, Juan Miguel Faltas, Bishoy M. Nat Commun Article The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients. Nature Publishing Group UK 2020-12-03 /pmc/articles/PMC7713129/ /pubmed/33273457 http://dx.doi.org/10.1038/s41467-020-19971-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Vosoughi, Aram
Zhang, Tuo
Shohdy, Kyrillus S.
Vlachostergios, Panagiotis J.
Wilkes, David C.
Bhinder, Bhavneet
Tagawa, Scott T.
Nanus, David M.
Molina, Ana M.
Beltran, Himisha
Sternberg, Cora N.
Motanagh, Samaneh
Robinson, Brian D.
Xiang, Jenny
Fan, Xiao
Chung, Wendy K.
Rubin, Mark A.
Elemento, Olivier
Sboner, Andrea
Mosquera, Juan Miguel
Faltas, Bishoy M.
Common germline-somatic variant interactions in advanced urothelial cancer
title Common germline-somatic variant interactions in advanced urothelial cancer
title_full Common germline-somatic variant interactions in advanced urothelial cancer
title_fullStr Common germline-somatic variant interactions in advanced urothelial cancer
title_full_unstemmed Common germline-somatic variant interactions in advanced urothelial cancer
title_short Common germline-somatic variant interactions in advanced urothelial cancer
title_sort common germline-somatic variant interactions in advanced urothelial cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713129/
https://www.ncbi.nlm.nih.gov/pubmed/33273457
http://dx.doi.org/10.1038/s41467-020-19971-8
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