Intra-tumour heterogeneity reflects cancer evolutionary dynamics: Implications for patient stratification


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Colin Watts1
1University of Cambridge, Cambridge, UK

Abstract

Gliomas are characterised by genetic instability and complex evolutionary dynamics. Histopathological diversity results in different clinical phenotypes, whose common feature is the rapid emergence of treatment resistance as a result of environmental selection pressures generated by radiotherapy and chemotherapy.

Recent models of gliomagenesis point to sub-ependymal neural stem cells (NSCs) as a putative cell of origin for astrocytic tumours and it has been shown that the stepwise pre-malignant loss of tumour suppressors p53, NF1 & PTEN1,2leads to the development of an aggressive disease phenotype characterised by resistance to genotoxic injury3,4. Although these observations reflect specific aspects of the clinical and biological diversity seen in patients, the human disease observed at presentation represents a complex clonal environment. In this context, the maintenance and growth of the cancer may depend on diverse tumorigenic cell populations that are distinct from any cell of origin5,6.

To interrogate genetic and clonal diversity we have developed FGMS (fluorescence-guided multiple sampling) that permits real-time spatially segregated tumour sampling during surgery allowing reconstruction of tumour phylogeny7,8. We have applied FGMS to glioblastoma to describe intra-tumoural heterogeneity, clonal diversity and infer phylogenetic architecture. Analysis of therapeutic responsiveness reveals diverse patterns within an individual tumour. Together these data reveal novel insights into the ontogeny, growth and response to treatment of glioblastoma at the level of the individual patient.

1. Zhu Y, et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 2005; 8(2):119-130.

2. Alcantara Llaguno S, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 2009;15(1):45-56.

3. Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444(7120):756-760.

4. Chen J, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012;488(7412):522-6.

5. Visvader JE. Cells of origin in cancer. Nature 2011;469(7330):314-22.

6. Sottoriva A, et al. Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer research 2013;73(1):41-9.

7. Piccirillo SG, et al. Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 2012;107(3):462-8.

8. Sottoriva A, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 2013;110(10):4009-14.