Takahashi T, Habuchi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Yoshida O
Department of Urology, Graduate School of Medicine, Kyoto University, Japan.
Cancer Res. 1998 Dec 15;58(24):5835-41.
Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The results indicate that most multifocal low-grade superficial urothelial cancers are genetically stable despite their incidence of frequent recurrence, and genetic divergence occurs in a subset of patients. This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers.
近期的分子遗传学研究表明，多灶性尿路上皮癌源自同一个祖细胞。然而，低级别浅表型多灶性尿路上皮癌的克隆起源尚未完全明确。我们使用微卫星标记，检测了87例异时性和/或同时性多灶性尿路上皮癌中8个染色体臂（2q、4p、4q、8p、9p、9q、11p和17p）上20个位点的基因改变，其中包括来自29例患者的84例低级别浅表乳头状肿瘤。从杂合性缺失模式、微卫星改变及亚染色体部分缺失情况判断，在25例可评估患者中，至少20例（80%）的多灶性肿瘤被认为源自单个祖细胞，不过仍存在一小部分患者的多灶性肿瘤可能因场癌化而源自不同祖细胞的可能性。在20例患者中的13例中，可进行时间顺序的基因分析：3例（23%）患者检测到基因异质性，仅1例（8%）患者检测到明显的基因改变累积模式。在20例克隆起源相同的多灶性肿瘤患者中，观察到微卫星改变不一致，与其他检测染色体相比，9号染色体上的频率显著更低。结果表明，大多数多灶性低级别浅表性尿路上皮癌尽管复发频繁，但基因稳定，且一部分患者会出现基因分歧。这种异位扩散和基因分歧可能在单个转化细胞出现多灶性临床表现之前很久就已发生。这些数据支持了之前的观点，即在大多数低级别浅表性尿路上皮癌中，转化祖细胞的异位扩散和基因分歧发生在9号染色体改变之后。
