Reifenberger Julia, Knobbe Christiane B, Wolter Marietta, Blaschke Britta, Schulte Klaus W, Pietsch Torsten, Ruzicka Thomas, Reifenberger Guido
Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany.
Int J Cancer. 2002 Aug 10;100(5):549-56. doi: 10.1002/ijc.10512.
Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.
Wnt信号通路的异常激活已在包括恶性黑色素瘤在内的不同人类肿瘤类型中被报道。我们研究了37例恶性黑色素瘤（15例原发性肿瘤和22例转移瘤）中该信号通路4个编码成员的基因改变，即CTNNB1（β-连环蛋白基因，3p22.1）、APC（腺瘤性息肉病基因，5q22.2）、BTRC（含β-转导蛋白重复序列的蛋白基因，10q24.3）和ICAT（β-连环蛋白和Tcf-4抑制剂，1p36.2）。CTNNB1的突变分析在2例不同患者的1例原发性黑色素瘤和1例黑色素瘤转移瘤中鉴定出体细胞突变（5%）。这两个突变均影响β-连环蛋白的N端降解框，该降解框对β-连环蛋白稳态的调节很重要。另一例原发性黑色素瘤在第15外显子的已知突变簇区域内发生了体细胞APC错义突变。14例肿瘤（40%）在1p36的微卫星标记处显示杂合性缺失。没有肿瘤丢失ICAT基因的两个拷贝，但1例黑色素瘤转移瘤发生了体细胞点突变，改变了ICAT的翻译起始密码子。实时逆转录聚合酶链反应显示，在36例恶性黑色素瘤中的28例（78%）中，ICAT转录水平显著降低（相对于正常皮肤和良性黑素细胞痣，≤20%），包括14例1p36杂合性缺失的肿瘤中的13例。15例肿瘤（44%）检测到10q等位基因缺失。在我们的黑色素瘤系列中，未发现BTRC基因的突变或完全表达缺失。综上所述，我们的结果表明，Wnt信号通路可能通过不同机制在恶性黑色素瘤中发生改变，包括CTNNB1、APC或ICAT中罕见的体细胞突变，以及ICAT转录本的低表达或无表达。
