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Serena Nik-Zainal

SNZ

Dr Serena Nik-Zainal

Biography | Publications

 

 

 

 

 

Physiology of mutagenesis

A cancer genome carries the scars of historic mutagenic activity that has occurred throughout the development of the tumour. While driver mutations were the main focus of cancer research for a long time, passenger mutations are also biologically informative. They report the DNA damage and DNA repair processes that have been operative during tumorigenesis, that leave characteristic imprints or mutational signatures in the developing cancer genome.

Previously, we were focused on computational delineation of mutational signatures in human cancers. More recently, we have become engrossed in experimental validation of mutational signatures to understand the etiologies that underpin them including environmental and endogenous DNA replicative/repair sources of mutagenesis. The insights that we have gained through combinations of computational analysis and experiments in cell-based systems has led to the development of clinical algorithmic tools that we intend to translate into clinical utility in the near future.

This lab studies the physiology of mutagenesis combining computational approaches with experimental and cancer data. We also seek clinical validity of our observations. We are a diverse group of individuals and are interested in hearing from anyone interested in joining the academic laboratory or clinical/genomic infrastructure team.

 

Mutational processes over the course of cancer development.

Each mutational process leaves a characteristic imprint — a mutational signature — in the cancer genome and comprises both a DNA damage component and a DNA repair component. 

In this hypothetical cancer genome, arrows indicate the duration and intensity of exposure to a mutational process. The final mutational portrait is the sum of all of the different mutational processes (A–D) that have been active in the entire lifetime. Ongoing mutational processes reflect active biological processes in the cancer that could be exploited either as biomarkers to monitor treatment response or as therapeutic anticancer targets. By contrast, historical mutational processes are no longer active. Signature A represents deamination of methylated cytosines, which is ongoing through life. Signature B can be matched up with the signatures of tobacco smoking, Signature C can represent bursts of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide)-induced deamination, and Signature D represents a DNA repair pathway that is awry. Image from Helleday, Eshtad and Nik-Zainal. Nat Rev Genet. 2014 Sep;15(9):585-98. 

 

 

 

 

Selected Publications:

Nik-Zainal S.

The duty to speak up

Nat Cell Biol. 2018 Sep;20(9):1006. doi: 10.1038/s41556-018-0171-7. 

 

Georgakopoulos-Soares I, Morganella S, Jain N, Hemberg M, Nik-Zainal S.

Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis.

Genome Res. 2018 Sep;28(9):1264-1271. doi: 10.1101/gr.231688.117. Epub 2018 Aug 13.

 

Zou X, Owusu M, Harris R, Jackson SP, Loizou J, Nik-Zainal S.

Validating the concept of mutational signatures with isogenic cell models.

Nature Communications 2018 May 1;9(1):1744. doi: 10.1038/s41467-018-04052-8.

 

Garaycoechea JI, Crossan GP, Langevin F, Mulderrig L, Louzada S, Yang F, Guilbaud G, Park N, Roerink S, Nik-Zainal S, Stratton MR, Patel KJ.

Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells. 

Nature. 2018 Jan 11;553(7687):171-177. doi: 10.1038/nature25154. Epub 2018 Jan 3. PubMed PMID: 29323295.

 

Zou X, Morganella S, Glodzik D, Davies H, Li Y, Stratton MR, Nik-Zainal S.

Short inverted repeats contribute to localized mutability in human somatic cells.

Nucleic Acids Res. 2017 Nov 2;45(19):11213-11221. doi: 10.1093/nar/gkx731.

 

Nik-Zainal S, Morganella S.

Mutational Signatures in Breast Cancer: The Problem at the DNA Level.

Clin Cancer Res. 2017 Jun 1;23(11):2617-2629. doi: 10.1158/1078-0432.CCR-16-2810.

 

Davies H, Morganella S, Purdie CA, Jang SJ, Borgen E, Russnes H, Glodzik D, Zou X, Viari A, Richardson AL, Børresen-Dale AL, Thompson A, Eyfjord JE, Kong G, Stratton MR, Nik-Zainal S.

Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency.

Cancer research. 2017; 77(18):4755-4762. PubMed PMID: 28904067

 

Davies H, Glodzik D, Morganella S, et al and Nik-Zainal S.

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Nature medicine. 2017; 23(4):517-525. PubMed PMID: 28288110

 

Glodzik D, Morganella S, Davies H, et al and Nik-Zainal S.

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.

Nature Genetics. 2017; 49(3):341-348. PubMed PMID: 28112740

 

Nik-Zainal S, Davies H, Staaf J, et al and Stratton MR.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Nature. 2016; 534(7605):47-54. NIHMSID: EMS68344 PubMed [journal] PMID: 27135926, PMCID: PMC4910866

 

Morganella S, Alexandrov LB, Glodzik D, et al and Nik-Zainal S.

The topography of mutational processes in breast cancer genomes.

Nature communications. 2016; 7:11383. PubMed PMID: 27136393, PMCID: PMC5001788


Rouhani FJ, Nik-Zainal S, Wuster A, Li Y, Conte N, Koike-Yusa H, Kumasaka N, Vallier L, Yusa K, Bradley A.

Mutational History of a Human Cell Lineage from Somatic to Induced Pluripotent Stem Cells.

PLoS Genet. 2016 Apr 7;12(4):e1005932. doi: 10.1371/journal.pgen.1005932. eCollection 2016 Apr.