Whole genome sequencing of matched primary and metastatic acral melanomas

Samra Turajlic, Simon J. Furney, Maryou B. Lambros, Costas Mitsopoulos, Iwanka Kozarewa, Felipe C. Geyer, Alan MacKay, Jarle Hakas, Marketa Zvelebil, Christopher J. Lord, Alan Ashworth, Meirion Thomas, Gordon Stamp, James Larkin, Jorge S. Reis-Filho, Richard Marais

Research output: Contribution to journalArticlepeer-review

Abstract

Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sunprotected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion. © 2012 by Cold Spring Harbor Laboratory Press.
Original languageEnglish
Pages (from-to)196-207
Number of pages11
JournalGenome research
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2012

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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