title: Whole genome sequencing of matched primary and metastatic acral melanomas.
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 sun-protected, 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.
authors.affiliation: Signal Transduction Team, Division of Cancer Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom.
authors.forename: Samra
authors.initials: S
authors.lastname: Turajlic
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Jarle
authors.initials: J
authors.lastname: Hakas
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Meirion
authors.initials: M
authors.lastname: Thomas
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000368:Aged; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D059645:Mutation Rate; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide