Papadimitrakopoulou V A, Oh Y, El-Naggar A, Izzo J, Clayman G, Mao L
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1998 Mar;4(3):539-44.
The 18q chromosomal region is frequently lost in head and neck squamous cell carcinomas (HNSCCs). Several candidate tumor suppressor genes have been mapped to this chromosomal region, including DCC, DPC4, and MADR2. The latter two genes are members of the Smad family, key downstream mediators in the transforming growth factor beta signaling pathway, and their alterations could confer resistance to transforming growth factor beta and contribute to tumorigenesis. Nevertheless, genetic alterations of DCC and DPC4 in HNSCC have not been frequently reported. To further investigate the extent and significance of the loss of the 18q chromosomal region in HNSCC, we performed detailed mapping at this region in a set of 50 primary HNSCCs using 19 highly polymorphic microsatellite markers. We detected loss of heterozygosity in 84% of the tumors tested and were able to identify three minimal deleted regions encompassing markers D18S467-D18S474 at 18q12 (4 cM), D18S1099-D18S487 at 18q21.1 (3 cM), and D18S69-41 at 18q21.1-q21.2 (2 cM). Of these minimal deleted regions, only one harbors a known candidate tumor suppressor gene, DCC, which maps telomeric to D18S46. In addition, the role of the MADR2 gene in HNSCCs was investigated by examining nine HNSCC cell lines for alterations of the gene by reverse transcription-PCR and direct sequencing analysis. No mutations or polymorphisms were detected, making this gene an unlikely target of the frequent loss at 18q in HNSCC. Our data indicate high frequency of loss of heterozygosity at 18q in HNSCC and the presence of at least two as yet unidentified tumor suppressor genes in this chromosomal region. Additional efforts to identify these putative tumor suppressor genes are warranted.
18号染色体区域在头颈部鳞状细胞癌（HNSCC）中经常缺失。几个候选肿瘤抑制基因已被定位到该染色体区域，包括DCC、DPC4和MADR2。后两个基因是Smad家族的成员，是转化生长因子β信号通路中的关键下游介质，它们的改变可能导致对转化生长因子β的抗性并促进肿瘤发生。然而，HNSCC中DCC和DPC4的基因改变尚未被频繁报道。为了进一步研究18号染色体区域缺失在HNSCC中的程度和意义，我们使用19个高度多态性微卫星标记在一组50例原发性HNSCC中对该区域进行了详细定位。我们在84%的测试肿瘤中检测到杂合性缺失，并能够确定三个最小缺失区域，分别包含18q12（4 cM）处的标记D18S467 - D18S474、18q21.1（3 cM）处的D18S1099 - D18S487以及18q21.1 - q21.2（2 cM）处的D18S69 - 41。在这些最小缺失区域中，只有一个包含一个已知的候选肿瘤抑制基因DCC，它位于D18S46的端粒侧。此外，通过逆转录 - PCR和直接测序分析检查9种HNSCC细胞系中MADR2基因的改变，以研究该基因在HNSCC中的作用。未检测到突变或多态性，这使得该基因不太可能是HNSCC中18q频繁缺失的靶点。我们的数据表明HNSCC中18q杂合性缺失的频率很高，并且该染色体区域存在至少两个尚未鉴定的肿瘤抑制基因。有必要进一步努力鉴定这些假定的肿瘤抑制基因。
