Toomes Carmel, Jackson Andrew, Maguire Kristie, Wood Joseph, Gollin Susanne, Ishwad Chandramohan, Paterson Ian, Prime Steven, Parkinson Kenneth, Bell Sandra, Woods Geoffrey, Markham Alexander, Oliver Richard, Woodward Robert, Sloan Philip, Dixon Michael, Read Andrew, Thakker Nalin
Department of Medical Genetics, University of Manchester, Manchester, United Kingdom.
Genes Chromosomes Cancer. 2003 Jun;37(2):132-40. doi: 10.1002/gcc.10191.
We and others previously identified a region of hemizygous or homozygous deletion at chromosome band 8p23 in oral and oropharyngeal squamous cell carcinomas (OSCCs) and many other cancer types, suggesting the presence of a tumor-suppressor gene (TSG) in this region. Recently, based on a single region of homozygous deletion in head and neck squamous cell carcinomas (HNSCC), a putative TSG, CUB and sushi multiple domains-1 (CSMD1), has been identified. In the present study, we mapped three OSCC cell lines with previously described homozygous deletions at a high resolution onto a detailed physical map. Critically, this map covered a wider region than that used in previous studies, and in contrast to these studies, our results revealed multiple regions of homozygous deletion within a small interval on 8p23. To investigate this deletion pattern further, we generated a panel of 34 sequence tagged site (STS) markers spanning the region and tested these three cell lines and an additional 34 OSCC cell lines, identifying homozygous deletions in a further four. Combining the results from all seven deleted cell lines identified three non-overlapping regions of homozygous deletion. This complex pattern could be consistent with the presence of multiple TSGs or one very large TSG in this region, and/or specific chromosomal instability. CSMD1 spans two of the three deleted regions and, therefore, would appear to be an excellent candidate for a TSG. However, deletion mapping with STSs corresponding to the exons of CSMD1 shows that some of the deletions do not interrupt its coding region, and in other cell lines the coding region is interrupted by two discontinuous homozygous deletions, suggesting the presence of redundant deletions. These results call into question whether the CSMD1 gene is the 8p23 TSG or whether this or any other genes at this locus are involved in the development of OSCC.
我们和其他研究团队之前在口腔和口咽鳞状细胞癌（OSCC）以及许多其他癌症类型中，发现了8号染色体p23带存在半合子或纯合子缺失区域，这表明该区域存在一个肿瘤抑制基因（TSG）。最近，基于头颈部鳞状细胞癌（HNSCC）中的一个纯合子缺失区域，一个假定的TSG——CUB和寿司多结构域-1（CSMD1）已被鉴定出来。在本研究中，我们将三个先前描述为存在纯合子缺失的OSCC细胞系以高分辨率定位到一个详细的物理图谱上。至关重要的是，该图谱覆盖的区域比先前研究中使用的区域更宽，并且与这些研究不同的是，我们的结果揭示了8p23上一个小间隔内存在多个纯合子缺失区域。为了进一步研究这种缺失模式，我们生成了一组跨越该区域的34个序列标签位点（STS）标记，并对这三个细胞系以及另外34个OSCC细胞系进行了检测，在另外四个细胞系中鉴定出了纯合子缺失。综合所有七个缺失细胞系的结果，确定了三个非重叠的纯合子缺失区域。这种复杂的模式可能与该区域存在多个TSG或一个非常大的TSG，和/或特定的染色体不稳定性相一致。CSMD1跨越了三个缺失区域中的两个，因此，似乎是TSG的一个极佳候选基因。然而，用与CSMD1外显子相对应的STS进行缺失定位表明，一些缺失并未中断其编码区，而在其他细胞系中，编码区被两个不连续的纯合子缺失中断，这表明存在冗余缺失。这些结果使人质疑CSMD1基因是否就是8p23的TSG，或者该位点的这个或任何其他基因是否参与了OSCC的发生发展。
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