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In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors
Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hy...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932606/ https://www.ncbi.nlm.nih.gov/pubmed/29632087 http://dx.doi.org/10.1101/gr.230219.117 |
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author | Boot, Arnoud Huang, Mi Ni Ng, Alvin W.T. Ho, Szu-Chi Lim, Jing Quan Kawakami, Yoshiiku Chayama, Kazuaki Teh, Bin Tean Nakagawa, Hidewaki Rozen, Steven G. |
author_facet | Boot, Arnoud Huang, Mi Ni Ng, Alvin W.T. Ho, Szu-Chi Lim, Jing Quan Kawakami, Yoshiiku Chayama, Kazuaki Teh, Bin Tean Nakagawa, Hidewaki Rozen, Steven G. |
author_sort | Boot, Arnoud |
collection | PubMed |
description | Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence. |
format | Online Article Text |
id | pubmed-5932606 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59326062018-11-01 In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors Boot, Arnoud Huang, Mi Ni Ng, Alvin W.T. Ho, Szu-Chi Lim, Jing Quan Kawakami, Yoshiiku Chayama, Kazuaki Teh, Bin Tean Nakagawa, Hidewaki Rozen, Steven G. Genome Res Research Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence. Cold Spring Harbor Laboratory Press 2018-05 /pmc/articles/PMC5932606/ /pubmed/29632087 http://dx.doi.org/10.1101/gr.230219.117 Text en © 2018 Boot et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Boot, Arnoud Huang, Mi Ni Ng, Alvin W.T. Ho, Szu-Chi Lim, Jing Quan Kawakami, Yoshiiku Chayama, Kazuaki Teh, Bin Tean Nakagawa, Hidewaki Rozen, Steven G. In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title | In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title_full | In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title_fullStr | In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title_full_unstemmed | In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title_short | In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
title_sort | in-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932606/ https://www.ncbi.nlm.nih.gov/pubmed/29632087 http://dx.doi.org/10.1101/gr.230219.117 |
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