Genomic profiling of malignant melanoma using tiling-resolution arrayCGH
Genomic profiling of malignant melanoma using tiling-resolution arrayCGH
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DOI：
10.1038/sj.onc.1210252
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发表时间：
2007-07-12
期刊：
影响因子：
8
通讯作者：
Borg, A.
中科院分区：
文献类型：
--
作者：
Joensson, G.;Dahl, C.;Borg, A.
恶性黑色素瘤是一种侵袭性、异质性疾病，需要新的生物标志物用于诊断和临床结局。我们使用47种不同的黑色素瘤细胞系和平铺分辨率细菌人工染色体阵列进行比较基因组杂交，寻找其发病机制的染色体畸变特征。检查主要黑色素瘤基因，包括BRAF、NRAS、CDKN 2A、TP 53、CTNNB 1、CDK 4和PTEN的突变。检测到不同的拷贝数改变，包括整个染色体的丢失或获得，但也有微小的扩增和纯合缺失。最常见的重叠区域与损失被定位到9p24.3-q13，10和11q14.1-qter，而拷贝数增益是最常见的染色体1 q，7，17 q和20 q。MITF（3 p14）、CCND 1（11 q13）、MDM 2（12 q15）、CCNE 1（19 q12）和NOTCH 2（1 p12）等癌基因扩增。在9 p21和10 q23上频繁的纯合性缺失的发现证实了CDKN 2A和PTEN的重要性。成对比较揭示了不同的改变组，例如，BRAF和NRAS中的互斥突变，BRAF和PTEN中的相互突变，伴随的7号染色体获得和10号染色体丢失以及伴随的15q22.2-q26.3获得和20号染色体获得。此外，各种黑色素瘤基因的改变与不同的染色体不平衡有关，提示黑色素瘤发展中的特定基因组程序。
Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.