Edwards Joanne, Duncan Pamela, Going James J, Watters Amanda D, Grigor Kenneth M, Bartlett John M S
University Department of Surgery, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.
J Pathol. 2002 Apr;196(4):380-5. doi: 10.1002/path.1052.
Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence.
在早期一项将9号染色体单体性与膀胱移行细胞癌（TCC）复发联系起来的研究之后，对109例原发性和复发性TCC（来自47例患者）进行了检查，以探索与复发相关的9号染色体上的基因改变。从存档组织切片中显微切割并提取患者DNA，分析9号染色体上已知存在肿瘤抑制基因（TSG）的三个区域（INK 4A、DBC1和TSC1）的杂合性缺失（LOH）。患者被分为两组，非复发性TCC（NR，n = 18）和复发性TCC（REC，n = 29）。值得注意的是，在跨越TSC1区域的所有信息性标记上，12%的NR肿瘤存在LOH，而REC原发性肿瘤为54%（p = 0.01）。TSC1缺失的患者复发风险显著高于保留TSC1区域的患者（p = 0.035）。NR肿瘤中DBC1或INK 4A的LOH水平与REC原发性肿瘤相比无显著差异，这两个基因的缺失均不影响无复发生存率。0%的NR肿瘤出现跨越9号染色体的所有信息性标记缺失，而REC原发性肿瘤为25%（p = 0.04）。在跨越9号染色体的所有信息性标记上存在LOH的患者复发概率也显著增加（p = 0.016），这证实了早期荧光原位杂交结果。这项研究进一步证明膀胱癌复发是一个独特的事件，具有潜在的分子原因。它还将TSC1基因座确定为TSG的候选基因，该基因在一部分TCC患者中驱动复发。包括位于TSC1区域的标记在内的跨越9号染色体的所有信息性标记缺失也与复发有关。
