Nowacki S, Skowron M, Oberthuer A, Fagin A, Voth H, Brors B, Westermann F, Eggert A, Hero B, Berthold F, Fischer M
Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany.
Oncogene. 2008 May 22;27(23):3329-38. doi: 10.1038/sj.onc.1210996. Epub 2007 Dec 17.
Cell adhesion molecule 1 (CADM1) is a putative tumour suppressor gene, which is downregulated in many solid tumours. In neuroblastoma, loss of CADM1 expression has recently been found in disseminated tumours with adverse outcome, prompting us to investigate its role in neuroblastoma tumour progression. Oligonucleotide-microarray analysis of 251 neuroblastoma specimens demonstrated that CADM1 downregulation is associated with unfavourable prognostic markers like disseminated stage 4, age >18 months, MYCN amplification and chromosome 11q alterations (P<0.001 each). Furthermore, low CADM1 expression was significantly correlated with unfavourable gene expression-based classification (P<0.001) and adverse patient outcome (P<0.001). Bisulphite sequencing and genetic analysis of 18 primary neuroblastomas suggested that neither haploinsufficiency nor hypermethylation is regularly involved in CADM1 gene silencing in neuroblastoma, which is in contrast to results obtained in other malignancies. In addition, no mutations disrupting the CADM1 reading frame were found in 25 primary neuroblastomas. Over-expression of CADM1 in neuroblastoma cells resulted in significant reduction of proliferation, viability and colony formation in soft agar. Collectively, our results suggest that downregulation of CADM1 tumour suppressor gene expression is a critical event in neuroblastoma pathogenesis resulting in tumour progression and unfavourable patient outcome.
细胞黏附分子1（CADM1）是一种假定的肿瘤抑制基因，在许多实体瘤中表达下调。在神经母细胞瘤中，最近发现在播散性肿瘤中CADM1表达缺失与不良预后相关，这促使我们研究其在神经母细胞瘤肿瘤进展中的作用。对251例神经母细胞瘤标本进行的寡核苷酸微阵列分析表明，CADM1下调与不良预后标志物相关，如播散性4期、年龄>18个月、MYCN扩增和11号染色体q臂改变（每项P<0.001）。此外，低CADM1表达与基于基因表达的不良分类（P<0.001）和患者不良预后（P<0.001）显著相关。对18例原发性神经母细胞瘤进行亚硫酸氢盐测序和基因分析表明，单倍体不足和高甲基化均未经常参与神经母细胞瘤中CADM1基因的沉默，这与在其他恶性肿瘤中获得的结果相反。此外，在25例原发性神经母细胞瘤中未发现破坏CADM1读码框的突变。在神经母细胞瘤细胞中过表达CADM1导致软琼脂中细胞增殖、活力和集落形成显著减少。总体而言，我们的结果表明，CADM1肿瘤抑制基因表达下调是神经母细胞瘤发病机制中的一个关键事件，导致肿瘤进展和患者不良预后。
