Ongoing_mutagenesis_RNAseq

One of the key questions to be explored is whether the biological processes generating specific mutational signatures continue to operate in the human cancer cell lines or simply reflect past mutagenic activity which is no longer operative. To address this question, we have extracted mutational signatures from 1,000 cancer cell lines of diverse cancer types. Several cell lines with mutational signatures of interest were selected, subcloned over a defined period of time and their genomes sequenced. The increased load of the mutations representative of a specific mutational signature within the genome of a subclone when compared to its parental clone was informative of the on-going mutational processes. To further study the recent observation that some of the clones belonging to a same cell line acquired differencet numbers of mutations over a set period of time, their RNA will be subjected to RNA-sequencing to study their differences.

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001004202	Multiple signatures of somatic mutations have been identified in human cancer genomes. To investigate whether mutational signatures continue to be generated, and if so their temporal patterns of activity, subsets of cell lines were cultured in vitro for extended periods and subjected to single cell cloning and whole genome or exome sequencing or directly to single cell whole genome sequencing. As expected, signatures of past exogenous exposures, such as tobacco smoke and ultraviolet light, were not generated in vitro. In contrast, signatures of normal and defective DNA repair and replication continued to be generated at essentially constant mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing activity exhibited a distinctive pattern with substantial fluctuations in mutation rate over time and episodic bursts of mutations. The initiating factors for these bursts are unclear although retrotransposon mobilisation may play a role. This cell line set now constitutes a comprehensive resource of live experimental models of mutational processes of both known and unknown aetiologies potentially retaining the patterns of activity and regulatory influences operative in human cells in vivo.	Illumina HiSeq 2500	26

Publications	Citations
Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis. Petljak M, Alexandrov LB, Brammeld JS, Price S, Wedge DC, Grossmann S, Dawson KJ, Ju YS, Iorio F, Tubio JMC, Koh CC, Georgakopoulos-Soares I, Rodríguez-Martín B, Otlu B, O'Meara S, Butler AP, Menzies A, Bhosle SG, Raine K, Jones DR, Teague JW, Beal K, Latimer C, O'Neill L, Zamora J, Anderson E, Patel N, Maddison M, Ng BL, Graham J, Garnett MJ, McDermott U, Nik-Zainal S, Campbell PJ, Stratton MR. Cell 176: 2019 1282-1294.e20	229

Publications

Citations

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.
Petljak M, Alexandrov LB, Brammeld JS, Price S, Wedge DC, Grossmann S, Dawson KJ, Ju YS, Iorio F, Tubio JMC, Koh CC, Georgakopoulos-Soares I, Rodríguez-Martín B, Otlu B, O'Meara S, Butler AP, Menzies A, Bhosle SG, Raine K, Jones DR, Teague JW, Beal K, Latimer C, O'Neill L, Zamora J, Anderson E, Patel N, Maddison M, Ng BL, Graham J, Garnett MJ, McDermott U, Nik-Zainal S, Campbell PJ, Stratton MR. Cell 176: 2019 1282-1294.e20

229