Zhuang S M, Eklund L K, Cochran C, Rao G N, Wiseman R W, Söderkvist P
Department of Occupational and Environmental Medicine, Faculty of Health Sciences, University Hospital, Linkoping University, Sweden.
Cancer Res. 1996 Jul 15;56(14):3338-43.
To identify potential tumor suppressor genes involved in lymphoma development, we generated allelotypes of 16 2',3'-dideoxycytidine (ddC and 31 1,3-butadiene (BD)-induced lymphomas from C57BL/6 x C3H/He F1 (hereafter called B6C3F1) mice. Two or more anonymous simple sequence length polymorphisms per autosome were examined for loss of heterozygosity (LOH). Allelic losses throughout the genome were generally infrequent, except for markers on chromosome 2, 4, 11 and 12. The highest frequency of allelic losses was observed on chromosome 12, with 38 and 39% in ddC and BD-induced lymphomas, respectively. The most prevalent LOH was localized to the distal region bounded by markers D12Mit263 and D12Nds2. No known tumor suppressor genes have been mapped to this region, and no obvious candidates could be identified, suggesting the presence of novel suppressor gene(s). LOH on chromosome 2 was observed in 31% of ddC-induced lymphomas but in only 3% (1/31) of BD-induced lymphomas, suggesting a ddC-specific genetic effect. Detailed analysis localized a potential tumor suppressor gene residing on the distal region of chromosome 2, between markers D2Mit147 and D2Mit148. Twenty-five % of ddC-induced and 23% of BD-induced lymphomas showed LOH on chromosome 4, and two discrete regions were identified. One of the regions includes the IFN gene cluster and is syntenic to human chromosome 9p2l-22. Candidate tumor suppressor genes, Mts1 (multiple tumor suppressor 1) and Mts2 have been mapped to this region. The second region is located on the distal part of chromosome 4, which is homologous to human chromosome 1p35-36, a region that is frequently deleted in various types of human tumors. Finally, 19% of ddC-induced and 29% of BD-induced lymphomas revealed LOH on chromosome 11 at the Acrb locus, which lies within 1 cM of p53, suggesting that the p53 tumor suppressor gene also plays a role in lymphomagenesis. These results suggest that multiple potential suppressor loci contribute to lymphoma development in B6C3F1 mice.
为了鉴定参与淋巴瘤发生的潜在肿瘤抑制基因，我们构建了16种2',3'-二脱氧胞苷（ddC）和31种1,3-丁二烯（BD）诱导的C57BL/6×C3H/He F1（以下称为B6C3F1）小鼠淋巴瘤的等位基因型。对每个常染色体上两个或更多的匿名简单序列长度多态性进行杂合性缺失（LOH）检测。除了2号、4号、11号和12号染色体上的标记外，全基因组的等位基因缺失通常很少见。在12号染色体上观察到最高频率的等位基因缺失，在ddC和BD诱导的淋巴瘤中分别为38%和39%。最普遍的LOH定位于由标记D12Mit263和D12Nds2界定的远端区域。尚无已知的肿瘤抑制基因定位于该区域，也未鉴定出明显的候选基因，提示存在新的抑制基因。在31%的ddC诱导的淋巴瘤中观察到2号染色体上的LOH，但在BD诱导的淋巴瘤中仅为3%（1/31），提示存在ddC特异性遗传效应。详细分析定位了一个潜在的肿瘤抑制基因位于2号染色体的远端区域，在标记D2Mit147和D2Mit148之间。25%的ddC诱导的淋巴瘤和23%的BD诱导的淋巴瘤在4号染色体上显示LOH，并鉴定出两个离散区域。其中一个区域包括IFN基因簇，与人9号染色体p2l-22同线。候选肿瘤抑制基因Mts1（多重肿瘤抑制因子1）和Mts2已定位于该区域。第二个区域位于4号染色体的远端，与人1号染色体p35-36同源，该区域在各种类型的人类肿瘤中经常缺失。最后，19%的ddC诱导的淋巴瘤和29%的BD诱导的淋巴瘤在位于p53 1 cM范围内的Acrb位点处的11号染色体上显示LOH，提示p53肿瘤抑制基因也在淋巴瘤发生中起作用。这些结果提示多个潜在的抑制基因座参与了B6C3F1小鼠淋巴瘤的发生。
