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Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes.

Publication ,  Journal Article
Parker, SCJ; Gartner, J; Cardenas-Navia, I; Wei, X; Ozel Abaan, H; Ajay, SS; Hansen, NF; Song, L; Bhanot, UK; Killian, JK; Gindin, Y ...
Published in: PLoS Genet
2012

Much emphasis has been placed on the identification, functional characterization, and therapeutic potential of somatic variants in tumor genomes. However, the majority of somatic variants lie outside coding regions and their role in cancer progression remains to be determined. In order to establish a system to test the functional importance of non-coding somatic variants in cancer, we created a low-passage cell culture of a metastatic melanoma tumor sample. As a foundation for interpreting functional assays, we performed whole-genome sequencing and analysis of this cell culture, the metastatic tumor from which it was derived, and the patient-matched normal genomes. When comparing somatic mutations identified in the cell culture and tissue genomes, we observe concordance at the majority of single nucleotide variants, whereas copy number changes are more variable. To understand the functional impact of non-coding somatic variation, we leveraged functional data generated by the ENCODE Project Consortium. We analyzed regulatory regions derived from multiple different cell types and found that melanocyte-specific regions are among the most depleted for somatic mutation accumulation. Significant depletion in other cell types suggests the metastatic melanoma cells de-differentiated to a more basal regulatory state. Experimental identification of genome-wide regulatory sites in two different melanoma samples supports this observation. Together, these results show that mutation accumulation in metastatic melanoma is nonrandom across the genome and that a de-differentiated regulatory architecture is common among different samples. Our findings enable identification of the underlying genetic components of melanoma and define the differences between a tissue-derived tumor sample and the cell culture created from it. Such information helps establish a broader mechanistic understanding of the linkage between non-coding genomic variations and the cellular evolution of cancer.

Duke Scholars

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2012

Volume

8

Issue

8

Start / End Page

e1002871

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Regulatory Sequences, Nucleic Acid
  • Primary Cell Culture
  • Polymorphism, Single Nucleotide
  • Neoplasm Metastasis
  • Melanoma
  • Melanocytes
  • Male
  • Humans
  • Genome-Wide Association Study
 

Citation

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Parker, S. C. J., Gartner, J., Cardenas-Navia, I., Wei, X., Ozel Abaan, H., Ajay, S. S., … Margulies, E. H. (2012). Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes. PLoS Genet, 8(8), e1002871. https://doi.org/10.1371/journal.pgen.1002871
Parker, Stephen C. J., Jared Gartner, Isabel Cardenas-Navia, Xiaomu Wei, Hatice Ozel Abaan, Subramanian S. Ajay, Nancy F. Hansen, et al. “Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes.PLoS Genet 8, no. 8 (2012): e1002871. https://doi.org/10.1371/journal.pgen.1002871.
Parker SCJ, Gartner J, Cardenas-Navia I, Wei X, Ozel Abaan H, Ajay SS, et al. Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes. PLoS Genet. 2012;8(8):e1002871.
Parker, Stephen C. J., et al. “Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes.PLoS Genet, vol. 8, no. 8, 2012, p. e1002871. Pubmed, doi:10.1371/journal.pgen.1002871.
Parker SCJ, Gartner J, Cardenas-Navia I, Wei X, Ozel Abaan H, Ajay SS, Hansen NF, Song L, Bhanot UK, Killian JK, Gindin Y, Walker RL, Meltzer PS, Mullikin JC, Furey TS, Crawford GE, Rosenberg SA, Samuels Y, Margulies EH. Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes. PLoS Genet. 2012;8(8):e1002871.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2012

Volume

8

Issue

8

Start / End Page

e1002871

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Regulatory Sequences, Nucleic Acid
  • Primary Cell Culture
  • Polymorphism, Single Nucleotide
  • Neoplasm Metastasis
  • Melanoma
  • Melanocytes
  • Male
  • Humans
  • Genome-Wide Association Study