Integrative analysis of chromosomal instability and tumor heterogeneity in cancer.

Collaborators:

• Charles Swanton
  Cancer Research UK, London Research Institute, Lincoln’s Inn Fields Laboratories
  http://www.london-research-institute.org.uk/research/152
  
  
• Zoltan Szallasi
  Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark
  http://www.cbs.dtu.dk/staff/show-staff.php?id=647

Cancer patients develop various types of genetic instabilities leading to phenotypes which give cancer cells evolutionary advantages compared to their non-cancer counterparts. A very common form of genetic instability is chromosomal instability (CIN), where parts of chromosomes or whole chromosomes are lost or gained at an increased rate. Although chromosomal instability is associated with chemotherapeutic drug resistance and worse clinical outcome, the development of CIN and its role in cancer progression is purely understood. In a close collaboration with clinicians and cancer biologists, we aim to use computational and statistical methods to develop a better understanding of CIN.

To get new insights in the causes and consequences of chromosomal instability, we firstly identify gene expression signatures which are likely to be involved in the development of CIN and secondly detect genes which are likely to give a fitness advantage to patients showing chromosomal instability. This is achieved by using large scale microarray expression, SNP array and sequencing experiments from public databases in addition to data produced by our collaborators.

Recently, we compared a set of near diploid colorectal cancer cell lines with a set of aneuploidy colorectal cancer cell lines for differences in drug resistance. We showed, that aneuploid cell lines are more resistant to a wide range of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. We were not able to identify a single drug were aneuploid cell lines showed increased sensitivity compared to the near diploid samples.

Although CIN is widely held to be associated with poor prognosis in solid tumours, evidence from pre-clinical and mouse tumour models suggest that CIN may paradoxically enhance or impair cancer cell fitness. We and colleagues showed recently, that ER(-) breast cancer patients with extreme degrees of CIN show improved clinical outcome compared to patients with intermediate degrees of CIN. This was shown when CIN was estimated by surrogate measures based on microarray expression as well as by direct assessment of CIN via centromeric FISH. Increasing CIN to a degree which is lethal for the cancer cell might be a future opportunity for the treatment of cancer.  

Endesfelder D, McGranahan N, Birkbak NJ, Szallasi Z, Kschischo M, Graham TA, Swanton C. A breast cancer meta-analysis of two expression measures of chromosomal instability reveals a relationship with younger age at diagnosis and high risk histopathological variables. Oncotarget. 2011 Jul;2(7):529-37.

Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA, Downward J, Szallasi Z, Tomlinson IP, Howell M, Kschischo M, Swanton C. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 2011 Mar 1;71(5):1858-70.

    Lee AJ, Roylance R, Sander J, Gorman P, Endesfelder D, Kschischo M, Jones NP, East P, Nicke B, Spassieva S, Obeid LM, Birkbak NJ, Szallasi Z, McKnight NC, Rowan AJ, Speirs V, Hanby AM, Downward J, Tooze SA, Swanton C. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. J Pathol. 2012 Feb;226(3):482-94. 

    Roylance R, Endesfelder D, Gorman P, Burrell RA, Sander J, Tomlinson I, Hanby AM, Speirs V, Richardson AL, Birkbak NJ, Eklund AC, Downward J, Kschischo M, Szallasi Z, Swanton C. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2183-94. 

    Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q, Hardcastle T, Lee A, Roy R, East P, Kschischo M, Endesfelder D, Wylie P, Kim SN, Chen JG, Howell M, Ried T, Habermann JK, Auer G, Brenton JD, Szallasi Z, Downward J. Chromosomal instability determines taxane response. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8671-6.