Takebayashi S, Ogawa T, Jung K Y, Muallem A, Mineta H, Fisher S G, Grenman R, Carey T E
Laboratory of Head and Neck Cancer Biology, The University of Michigan, Ann Arbor, 48109-0506, USA.
Cancer Res. 2000 Jul 1;60(13):3397-403.
Loss of heterozygosity (LOH) on 18q predicts poor survival in head and neck squamous cell carcinomas (HNSCCs). Several putative tumor suppressor genes, such as DCC, DPC4/Smad4, and MADR2/Smad2, are mapped to 18q, but thus far, the important gene locus in HNSCC is not known. To identify possible gene loci on 18q, we performed LOH studies using tumor DNA from 57 HNSCC primary tumor cell lines and DNA isolated from fibroblasts or lymphoblastoid cells from the same patients. Forty-two highly polymorphic microsatellite markers spaced not more than 5 cM apart (mean distance, 1.82 cM) spanning the region from D18S44 in 18q11.1 to D18S1141 in 18q23 were used. D18S71 in 18p11.21 on 18p was also used to determine whether the short arm was retained. Forty-three of 57 (75%) HNSCC lines showed LOH or isolated allelic imbalance (AI) for at least one locus on 18q. Although many of the cell lines had large distal 18q deletions with a breakpoint between 18q11.1 and 18q12.2 to qter, three loci were identified that were lost in 70% or more of the cases. The minimally lost regions (MLRs) range in size from 1.5-15.79 cM. The most proximal is centered on D18S39 (1.56 cM) in band 18q21.1, with LOH or isolated AI in 28 of 38 (74%) of informative cases. The largest (15.8 cM) begins at D18S61 (28 of 40; 70%) in band 18q22.2 and extends through D18S50 in 18q23. The third is centered on D18S70 (30 of 40; 75%) in band 18q23 (3.67 cM). Of these MLRs, only the one centered on D18S39 has been implicated previously in HNSCC. D18S70, the most frequently lost marker, was the only marker consistently lost in three tumor cell lines with very minimal losses, UM-SCC-19, UM-SCC-67, and UM-SCC-73A. In addition, UM-SCC-91 exhibited AI only at this locus, and UT-SCC-4 had AI at D18S70 and D18S39 only. Close physical mapping of these three regions may pinpoint one or more previously unidentified tumor suppressor genes.
18号染色体长臂杂合性缺失（LOH）预示着头颈部鳞状细胞癌（HNSCC）患者预后不良。几个假定的肿瘤抑制基因，如DCC、DPC4/Smad4和MADR2/Smad2，定位于18号染色体长臂，但迄今为止，HNSCC中的重要基因位点尚不清楚。为了确定18号染色体长臂上可能的基因位点，我们使用来自57例HNSCC原发性肿瘤细胞系的肿瘤DNA以及从同一患者的成纤维细胞或淋巴母细胞中分离的DNA进行了LOH研究。使用了42个高度多态性微卫星标记，它们相隔不超过5厘摩（平均距离为1.82厘摩），跨越从18q11.1的D18S44到18q23的D18S1141的区域。18号染色体短臂18p11.21上的D18S71也用于确定短臂是否保留。57个HNSCC细胞系中有43个（75%）在18号染色体长臂上至少有一个位点出现LOH或孤立的等位基因失衡（AI）。尽管许多细胞系在18号染色体长臂远端有大片段缺失，断点在18q11.1和18q12.2至qter之间，但确定了三个在70%或更多病例中缺失的位点。最小缺失区域（MLR）大小在1.5 - 15.79厘摩之间。最靠近近端的区域以18q21.1带中的D18S39（1.56厘摩）为中心，在38例信息性病例中有28例（74%）出现LOH或孤立的AI。最大的区域（15.8厘摩）从18q22.2带中的D18S61（40例中有28例；70%）开始，延伸至18q23中的D18S50。第三个区域以18q23带中的D18S70（40例中有30例；75%）为中心（3.67厘摩）。在这些MLR中，只有以D18S39为中心的区域先前在HNSCC中被提及。D18S70是最常缺失的标记，是在三个损失非常小的肿瘤细胞系UM - SCC - 19、UM - SCC - 67和UM - SCC - 73A中唯一始终缺失的标记。此外，UM - SCC - 91仅在该位点出现AI，而UT - SCC - 4仅在D18S70和D18S39出现AI。对这三个区域进行紧密的物理图谱绘制可能会确定一个或多个先前未被识别的肿瘤抑制基因。
