Advancing a clinically relevant perspective of the clonal nature of cancer
Open Access
- 5 July 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (29), 12054-12059
- https://doi.org/10.1073/pnas.1104009108
Abstract
Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing. The results produced high-definition genomic profiles of clonal populations from 40 pancreatic adenocarcinomas and a set of prostate adenocarcinomas, including serial biopsies from a patient who progressed to androgen-independent metastatic disease. The genomes of clonal populations were found to have patient-specific aberrations of clinical relevance. Furthermore, we identified genomic aberrations specific to therapeutically responsive and resistant clones arising during the evolution of androgen-independent metastatic prostate adenocarcinoma. We also distinguished divergent clonal populations within single biopsies and mapped aberrations in multiple aneuploid populations arising in primary and metastatic pancreatic adenocarcinoma. We propose that our high-definition analyses of the genomes of distinct clonal populations of cancer cells in patients in vivo can help guide diagnoses and tailor approaches to personalized treatment.Keywords
This publication has 50 references indexed in Scilit:
- Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapyEuropean Journal of Cancer, 2010
- The patterns and dynamics of genomic instability in metastatic pancreatic cancerNature, 2010
- ERG rearrangement is specific to prostate cancer and does not occur in any other common tumorLaboratory Investigation, 2010
- Genome remodelling in a basal-like breast cancer metastasis and xenograftNature, 2010
- Prevalence of TMPRSS2–ERG and SLC45A3–ERG gene fusions in a large prostatectomy cohortLaboratory Investigation, 2010
- A comprehensive catalogue of somatic mutations from a human cancer genomeNature, 2009
- A small-cell lung cancer genome with complex signatures of tobacco exposureNature, 2009
- NUMB controls p53 tumour suppressor activityNature, 2008
- Characterizing the cancer genome in lung adenocarcinomaNature, 2007
- High-throughput oncogene mutation profiling in human cancerNature Genetics, 2007