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Title: Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors.
Austin Authors: Anaka, Matthew;Hudson, Christopher;Lo, Pu-Han;Do, Hongdo;Caballero, Otavia L;Davis, Ian D;Dobrovic, Alexander ;Cebon, Jonathan S ;Behren, Andreas
Cancer Immuno-biology Lab, Ludwig Institute for Cancer Research Melbourne, Austin Branch, Melbourne, Victoria 3084, Australia
Issue Date: 11-Oct-2013
Publication information: Bmc Medical Genomics 2013; 6(): 40
Abstract: 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.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.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.Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma.
Gov't Doc #: 24119551
DOI: 10.1186/1755-8794-6-40
Journal: BMC medical genomics
Type: Journal Article
Subjects: Cell Line, Tumor
Clone Cells.pathology
DNA Copy Number Variations
Genetic Variation
Neoplasm Metastasis
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Appears in Collections:Journal articles

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