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Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction

Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutat...

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Autores principales: Koire, Amanda, Kim, Young Won, Wang, Jarey, Katsonis, Panagiotis, Jin, Haijing, Lichtarge, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370158/
https://www.ncbi.nlm.nih.gov/pubmed/28350864
http://dx.doi.org/10.1371/journal.pone.0174766
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author Koire, Amanda
Kim, Young Won
Wang, Jarey
Katsonis, Panagiotis
Jin, Haijing
Lichtarge, Olivier
author_facet Koire, Amanda
Kim, Young Won
Wang, Jarey
Katsonis, Panagiotis
Jin, Haijing
Lichtarge, Olivier
author_sort Koire, Amanda
collection PubMed
description Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development.
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spelling pubmed-53701582017-04-06 Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction Koire, Amanda Kim, Young Won Wang, Jarey Katsonis, Panagiotis Jin, Haijing Lichtarge, Olivier PLoS One Research Article Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development. Public Library of Science 2017-03-28 /pmc/articles/PMC5370158/ /pubmed/28350864 http://dx.doi.org/10.1371/journal.pone.0174766 Text en © 2017 Koire et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Koire, Amanda
Kim, Young Won
Wang, Jarey
Katsonis, Panagiotis
Jin, Haijing
Lichtarge, Olivier
Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title_full Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title_fullStr Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title_full_unstemmed Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title_short Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
title_sort codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370158/
https://www.ncbi.nlm.nih.gov/pubmed/28350864
http://dx.doi.org/10.1371/journal.pone.0174766
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