Genome instability and cell turnover in cancer

RESEARCH

Genome instability

Genomic aberrations in cancer cells are thought to arise through a gradual process of mutation and selection. According to this multi-step model of cancer development, the progressive accumulation of genomic changes leads to the activation of oncogenes and to the loss of tumor suppressor functions, which result in changes in cell function and transformation into malignant cells.

The increasing resolution of high-throughput genomic sequencing technologies has recently enabled the discovery of a novel phenomenon of genomic instability that plays a role in particular in cancer formation, where tens to hundreds of chromosome rearrangements localized to a limited number of genomic regions are acquired in a one-off catastrophic event. This form of genome instability was called chromothripsis (introduced by Stephens and coworkers; chromo stands for “chromosome” and thripsis describes the shattering process).

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Chromothripsis, a novel form of genomic instability
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Chromothripsis affects single chromosomes and/or chromosome regions that are shattered into numerous pieces. Subsequent imperfect repair processes lead to the formation of highly derivative chromosomes. Cells that survive such a drastic event likely have gained a strong selection advantage due to their vastly rearranged genome – a process that potentially transforms such cells into cancer cells. Importantly, the occurrence of chromothripsis was detected in a wide range of tumor entities and associated with poor prognosis (Rausch et al, Cell 2012; Rode & Maass et al, Int J Cancer 2016; Ernst et al, Int J Cancer 2016).

Our goal is to understand i) the mechanisms of chromothripsis initiation in cancer ii) the context of chromothripsis occurrence iii) how chromothriptic events may promote cancer development and iv) how these events may affect cancer therapy.

 

Cell turnover in cancer

Tumor formation can occur early in life and in some cases progress initially without major symptom over a long period of time or start relatively late and evolve as a fast process, which involves potential differences in terms of tumor cell dissemination processes, role of the immune system, and cell(s) of origin. We are interested in the time point of cancer development in humans. To address this question, we use retrospective birth-dating to determine the age of tumor cells (Ernst et al, Cell 2014).

Selected publications

Telomere dysfunction and chromothripsis.

Ernst A, Jones DT, Maass KK, Rode A, Deeg KI, Jebaraj BM, Korshunov A, Hovestadt V, Tainsky MA, Pajtler KW, Bender S, Brabetz S, Gröbner S, Kool M, Devens F, Edelmann J, Zhang C, Castelo-Branco P, Tabori U, Malkin D, Rippe K, Stilgenbauer S, Pfister SM, Zapatka M, Lichter P.

Int J Cancer. 2016 Jun 15;138(12):2905-14. doi: 10.1002/ijc.30033.

 

Chromothripsis in cancer cells: An update.

Rode A, Maass KK, Willmund KV, Lichter P, Ernst A.

Int J Cancer. 2016 May 15;138(10):2322-33. doi: 10.1002/ijc.29888. Review.

 

Adult neurogenesis in humans- common and unique traits in mammals.

Ernst A, Frisén J.

PLoS Biol. 2015 Jan 26;13(1):e1002045. doi: 10.1371/journal.pbio.1002045.

 

Neurogenesis in the striatum of the adult human brain.

Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisén J.

Cell. 2014 Feb 27;156(5):1072-83. doi: 10.1016/j.cell.2014.01.044.

 

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

Rausch T, Jones DT, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, Jäger N, Remke M, Shih D, Northcott PA, Pfaff E, Tica J, Wang Q, Massimi L, Witt H, Bender S, Pleier S, Cin H, Hawkins C, Beck C, von Deimling A, Hans V, Brors B, Eils R, Scheurlen W, Blake J, Benes V, Kulozik AE, Witt O, Martin D, Zhang C, Porat R, Merino DM, Wasserman J, Jabado N, Fontebasso A, Bullinger L, Rücker FG, Döhner K, Döhner H, Koster J, Molenaar JJ, Versteeg R, Kool M, Tabori U, Malkin D, Korshunov A, Taylor MD, Lichter P, Pfister SM, Korbel JO.

Cell. 2012 Jan 20;148(1-2):59-71. doi: 10.1016/j.cell.2011.12.013.

 

Group members

Frauke Devens, Kendra Maaß, Aurélie Ernst, Manasi Ratnaparkhe, Thorsten Kolb, Michaela Hergt
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Open positions

We have an open position for a Master Thesis for students of the Master programs MSc Biosciences, MSc Biotechnology or MSc Molecular Biomedicine.

Contact:
Dr. Aurélie Ernst
Team Leader
a.ernst@dkfz.de
Tel: +49-6221-42-1512

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