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The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models

Jennifer Yen1, Richard M White2, David C Wedge1, Peter Van Loo13, Jeroen de Ridder4, Amy Capper5, Jennifer Richardson5, David Jones1, Keiran Raine1, Ian R Watson6, Chang-Jiun Wu6, Jiqiu Cheng7, Iñigo Martincorena1, Serena Nik-Zainal1, Laura Mudie1, Yves Moreau7, John Marshall1, Manasa Ramakrishna1, Patrick Tarpey1, Adam Shlien1, Ian Whitmore1, Steve Gamble1, Calli Latimer1, Erin Langdon8, Charles Kaufman8, Mike Dovey8, Alison Taylor8, Andy Menzies1, Stuart McLaren1, Sarah O’Meara1, Adam Butler1, Jon Teague1, James Lister9, Lynda Chin10, Peter Campbell1, David J Adams1, Leonard I Zon8, E Elizabeth Patton5, Derek L Stemple1 and P Andy Futreal16*

Author Affiliations

1 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK

2 Memorial Sloan Kettering Cancer Center and Weill-Cornell Medical College, New York, NY 10065, USA

3 Department of Human Genetics, VIB and University of Leuven, B-3000, Leuven, Belgium

4 Delft Bioinformatics Lab, Delft University of Technology, Delft 2628CD, the Netherlands

5 MRC Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit and Edinburgh Cancer Research Centre, Edinburgh EH4 2XU, UK

6 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

7 Department of Electrical Engineering, University of Leuven, B-3001, Leuven, Belgium

8 Dana Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA

9 Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298-0033, USA

10 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

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Genome Biology 2013, 14:R113  doi:10.1186/gb-2013-14-10-r113

Published: 23 October 2013

Additional files

Additional file 1: Tables S1 to S10:

Table S1: zebrafish tumors used in the exome study. Table S2: sequencing coverage and metrics. Table S3: somatic mutations identified in the 53 zebrafish melanomas. Table S4: copy number changes identified in the 53 zebrafish melanomas. Table S5: P-values of genes occurring in amplifications. Table S6: P-values of genes occurring in homozygous deletions. Table S7: insertion and deletions identified in the 53 zebrafish melanomas. Table S8: statistical analysis of mutation burden correlation. Table S9: significance of genes with respect to frequency and modality. Table S10 Mutated pathways and their significance from enrichment analysis.

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Additional file 2: Figures S1 to S8:

Figure S1: effect of SNP density on germline and somatic substitution calling performance using CaVEMan. Figure S2: comparison of substitution calling algorithms on zebrafish melanoma data. Figure S3: experimental outline. Figure S4: evidence of two additional cluster of mutations in ZD8a on chromosome 10. Figure S5: comparison of copy number aberration profiles between ASCAT and aCGH. Figure S6: unsupervised clustering analysis of copy number aberrations. Figure S7: pathway analysis of all mutations. Figure S8: distribution of co-occurring copy number alterations and/or somatic mutations in TP53, MITF, and CDKN2A across 120 BRAF mutant melanomas identified in the SKCM TCGA dataset.

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Additional file 3:

Supplementary text describing the mutation calling simulations and comparison of mutation callers.

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