Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression.
Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression.
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DOI：
10.1038/sj.bjc.6606072
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发表时间：
2011-02-01
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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致癌的BRAF突变被认为是黑素细胞肿瘤形成的始祖事件；然而，我们最近通过在获得性黑素细胞痣中显示BRAF突变的显著多克隆性而反对这一观点(Lin等，J Natl癌症研究所，2009；101：1423-7)。在这里，我们测试了在原发性黑色素瘤中是否存在类似的BRAF突变的异质性。我们使用抗人高分子黑色素瘤相关抗原的抗体从五个原发黑色素瘤组织中分离并测序了单个黑色素瘤细胞。我们还通过检测BRAFV600E突变的敏感突变分析以及分离的等位基因的克隆和测序，对10例原发性黑色素瘤进行了检测。此外，我们估计了三名患者的原发肿瘤和复发或转移的配对样本中BRAF突变等位基因的频率。单细胞突变分析显示，五个原发黑色素瘤中有四个同时含有BRAF野生型和BRAF突变型肿瘤细胞。在10例原发黑色素瘤中，有8例表现出BRAF突变的肿瘤异质性。在所有三名患者中都证实了进展过程中BRAF突变等位基因的选择。BRAF突变的获得不是一个创始人事件，而可能是黑色素瘤发展过程中的多个克隆性事件之一，在黑色素瘤的进展过程中被选中。
Oncogenic BRAF mutation had been considered to be a founder event in the formation of melanocytic tumours; however, we recently argued against this notion by showing marked polyclonality of BRAF mutations in acquired melanocytic nevi (Lin et al, J Natl Cancer Inst., 2009; 101:1423–7). Here, we tested whether similar heterogeneity of BRAF mutations exists in primary melanomas. We isolated and sequenced single melanoma cells from five primary melanoma tissues using antibodies against human high-molecular-weight melanoma-associated antigen. We also examined 10 primary melanomas by the sensitive Mutector assay detecting the BRAFV600E mutation, as well as by cloning and sequencing of separated alleles. Furthermore, we estimated the frequency of BRAF mutant alleles in paired samples of primary tumour and recurrence or metastasis in three patients. Single-cell mutation analyses revealed that four of five primary melanomas contained both BRAF-wild-type and BRAF-mutant tumour cells. Tumour heterogeneity in terms of BRAF mutations was also shown in 8 of 10 primary melanomas. Selection of BRAF mutant alleles during progression was demonstrated in all the three patients. Acquisition of a BRAF mutation is not a founder event, but may be one of the multiple clonal events in melanoma development, which is selected for during the progression.
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DOI：
10.1038/jid.2008.374
发表时间：
2009-06
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
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影响因子：
2.2
作者：
Kirschner, M;Helmke, B;Deichmann, M
通讯作者：
Deichmann, M
影响因子：
10.3
作者：
Lin, Jingrong;Takata, Minoru;Saida, Toshiaki
通讯作者：
Saida, Toshiaki
影响因子：
5.2
作者：
Sala, Elisa;Mologni, Luca;Gambacorti-Passerini, Carlo
通讯作者：
Gambacorti-Passerini, Carlo
Naevi中的细胞衰老和黑色素瘤中的永生化：P16的作用？
影响因子：
8.8
作者：
Gray-Schopfer, V C;Cheong, S C;Chong, H;Chow, J;Moss, T;Abdel-Malek, Z A;Marais, R;Wynford-Thomas, D;Bennett, D C
通讯作者：
Bennett, D C