Whole genome sequencing of matched primary and metastatic acral melanomas
Whole genome sequencing of matched primary and metastatic acral melanomas
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DOI：
10.1101/gr.125591.111
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发表时间：
2012-02-01
期刊：
影响因子：
7
通讯作者：
Marais, Richard
中科院分区：
文献类型：
--
作者：
Turajlic, Samra;Furney, Simon J.;Marais, Richard
下一代测序使癌症样本突变谱的系统发现成为可能。在这里，我们使用全基因组测序来表征原发性肢端黑色素瘤及其淋巴结转移的体细胞突变和结构变异。我们的数据显示，与黑色素瘤细胞系基因组或黑色素瘤短期培养的转录组相比，该肢端黑色素瘤样本对的体细胞突变率更接近于与诱变暴露无关的癌症基因组中报告的突变率。尽管人们认为肢端皮肤是防晒的，但这些样本中的主要突变特征与紫外线照射造成的损伤是相容的。在原发性和转移性肿瘤中发现的ERCC5无义突变也可能通过未修复的双嘧啶病变的积累而导致突变特征。然而，转录区和表达基因的较低突变率表明了转录偶联修复的证据。原发和转移在基因拷贝数改变、杂合性缺失和单核苷酸变异（SNV）水平上高度相似。此外，原发肿瘤中的大多数SNV在转移中繁殖，转移灶中似乎重新出现了一个非同义编码SNV和一个剪接位点突变。
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.