Research Area
Dr. Petljak combines experimental and computational approaches to define active mutational processes in human cancer, study their occurrence and explore their underlying mechanisms. Ultimately, an understanding of on-going mutagenesis offers the potential to identify novel therapeutic targets and biomarkers for prognosis and therapeutic sensitivity in cancer patients. Dr. Petljak characterized human cancer cell models that actively acquire many of the mutational signatures identified in cancer and discerned signatures of ongoing from historic mutational processes. She found that unlike other mutagenic processes, mutagenesis attributed to APOBEC deaminases, prevalent in cancer, operates over episodic mutational bursts. In a subsequent study, Dr. Petljak showed that APOBEC3A enzymes mediates majority of APOBEC-related mutations, and dissected some of the underpinning DNA repair mechanisms that translate aberrant APOBEC activities into mutations.
Team Description
Every cancer cell carries a large number of mutations that are not implicated in oncogenesis but form characteristic patterns termed mutational signatures, which can inform on the sources of mutagenesis. Whereas mutations found in cancer DNA represent historical traces of mutational processes that were once operative, they lack the information on whether the mutagenesis remains switched ‘on’ or ‘off’ in cancer cells. We are using mutational signatures as a readout, and next-generation sequencing as a tool, to identify mutagenic activities that continue to operate during cancer development and progression. My further interests encompass identification of genes responsible for an active mutagenesis through application of CRISPR/Cas9 genome editing technology.
Team Members
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Publications
1.Petljak M, Dananberg A, Chu K, Bergstrom EN, Striepen J, von Morgen P, Chen Y, Shah H, Sale JE, Alexandrov LB, Stratton MR, Maciejowski J. Mechanisms of APOBEC3 mutagenesis in human cancer cells. Nature. 2022 Jul;607(7920):799-807. doi: 10.1038/s41586-022-04972-y. Epub 2022 Jul 20. PMID: 35859169; PMCID: PMC9329121.
2.Petljak M, Green AM, Maciejowski J, Weitzman MD. Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer. Nat Genet. 2022 Nov;54(11):1599-1608. doi: 10.1038/s41588-022-01196-8. Epub 2022 Oct 24. PMID: 36280735; PMCID: PMC9700387.
3.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. Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis. Cell. 2019 Mar 7;176(6):1282-1294.e20. doi: 10.1016/j.cell.2019.02.012. PMID: 30849372; PMCID: PMC6424819.
4.Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.Brammeld JS, Petljak M, Martincorena I, Williams SP, Alonso LG, Dalmases A, Bellosillo B, Robles-Espinoza CD, Price S, Barthorpe S et al.Genome research 2017;27;4;613-625
5.Understanding mutagenesis through delineation of mutational signatures in human cancer.Petljak M and Alexandrov LB Carcinogenesis 2016;37;6;531-40
6.Germline TERT promoter mutations are rare in familial melanoma.Harland M, Petljak M, Robles-Espinoza CD, Ding Z, Gruis NA, van Doorn R, Pooley KA, Dunning AM, Aoude LG, Wadt KA et al.Familial cancer 2016;15;1;139-44
7.Genome sequencing of normal cells reveals developmental lineages and mutational processes.Behjati S, Huch M, van Boxtel R, Karthaus W, Wedge DC, Tamuri AU, Martincorena I, Petljak M, Alexandrov LB, Gundem G et al.Nature 2014;513;7518;422-425
8.Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, Davies HR, Knappskog S, Martin S, Papaemmanuil E et al.Nature genetics 2014;46;5;487-91
9.POT1 loss-of-function variants predispose to familial melanoma.Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M et al.Nature genetics 2014;46;5;478-481