In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors
Mi Ni Huang,
Alvin WT Ng,
Jing Quan Lim,
Bin Tean Teh,
Steven G Rozen
Posted 17 Sep 2017
bioRxiv DOI: 10.1101/189233 (published DOI: 10.1101/gr.230219.117)
Posted 17 Sep 2017
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 non-invasive monitoring for secondary malignancies after cisplatin chemotherapy. Methods: 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 non-negative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. Results: 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 inter-strand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in 9 hepatocellular carcinomas and 3 esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. Conclusions: 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.
- Downloaded 648 times
- Download rankings, all-time:
- Site-wide: 20,465 out of 83,516
- In cancer biology: 623 out of 2,914
- Year to date:
- Site-wide: 65,476 out of 83,516
- Since beginning of last month:
- Site-wide: 69,199 out of 83,516
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!