期刊
BRITISH JOURNAL OF CANCER
卷 104, 期 3, 页码 464-468出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6606072
关键词
laser-capture microdissection; oncogene mutation; single-cell PCR; targeted therapy; V-raf murine sarcoma viral oncogene homologue B1
类别
资金
- Ministry of Health, Labor, and Welfare of Japan [15-10, 21S-7 (6)]
- Japan Society for the Promotion of Science [20591318]
- Ministry of Education, Culture, Sports and Technology of Japan
- Grants-in-Aid for Scientific Research [20591318] Funding Source: KAKEN
BACKGROUND: 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. METHODS: 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 BRAF(V600E) 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. RESULTS: 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. CONCLUSION: 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. British Journal of Cancer (2011) 104, 464-468. doi:10.1038/sj.bjc.6606072 www.bjcancer.com Published online 11 January 2011 (C) 2011 Cancer Research UK
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