Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors

BMC Medical Genomics

Andreas Behren³  Jonathan Cebon⁵  Alexander Dobrovic¹  Ian D Davis²  Otavia L Caballero⁶  Hongdo Do¹  Pu-Han Lo³  Christopher Hudson³  Matthew Anaka⁴ 

[1]Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia

[2]Current Address: Monash University and Eastern Health, Box Hill, Victoria 3128, Australia

[3]Cancer Immuno-biology Lab, Ludwig Institute for Cancer Research Melbourne, Austin Branch, Melbourne, Victoria 3084, Australia

[4]Department of Medicine, Austin Health, University of Melbourne, Parkville, Victoria 3010, Australia

[5]Ludwig Institute For Cancer Research, Level 5, Olivia Newton-John Cancer & Wellness Centre, Studley Road, Heidelberg, Victoria 3084, Australia

[6]Department of Neurosurgery, John Hopkins University School of Medicine, Baltimore, MD 21231, USA

关键词: Clonal;    Copy number;    Mutation profiling;    Heterogeneity;    Microarray;    Melanoma;   

Others  :  1091799
DOI  :  10.1186/1755-8794-6-40

 received in 2013-04-21, accepted in 2013-09-19,  发布年份 2013

【 摘 要 】

Background

Intratumoral heterogeneity is a major obstacle for the treatment of cancer, as the presence of even minor populations that are insensitive to therapy can lead to disease relapse. Increased clonal diversity has been correlated with a poor prognosis for cancer patients, and we therefore examined genetic, transcriptional, and functional diversity in metastatic melanoma.

Methods

Amplicon sequencing and SNP microarrays were used to profile somatic mutations and DNA copy number changes in multiple regions from metastatic lesions. Clonal genetic and transcriptional heterogeneity was also assessed in single cell clones from early passage cell lines, which were then subjected to clonogenicity and drug sensitivity assays.

Results

MAPK pathway and tumor suppressor mutations were identified in all regions of the melanoma metastases analyzed. In contrast, we identified copy number abnormalities present in only some regions in addition to homogeneously present changes, suggesting ongoing genetic evolution following metastatic spread. Copy number heterogeneity from a tumor was represented in matched cell line clones, which also varied in their clonogenicity and drug sensitivity. Minor clones were identified based on dissimilarity to the parental cell line, and these clones were the most clonogenic and least sensitive to drugs. Finally, treatment of a polyclonal cell line with paclitaxel to enrich for drug-resistant cells resulted in the adoption of a gene expression profile with features of one of the minor clones, supporting the idea that these populations can mediate disease relapse.

Conclusion

Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma.

【 授权许可】

   
2013 Anaka et al.; licensee BioMed Central Ltd.

【 图 表 】

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