尿路上皮発癌のInitiationとしての第9染色体の異常

Abstract

多発尿路上皮癌の経時的な遺伝子解析により, 1)おもに表在性の多発尿路上皮癌症例では, (少なくとも)約80%は同一クローン由来と考えられる.2)表在性尿路上皮癌の多くは再発を繰り返しても遺伝的には安定である.3)多発尿路上皮癌の腫瘍間での遺伝子変化の多様性は第9染色体の異常が生じた後に起る.4)第9染色体の異常が生じた後も臨床的に腫瘍を形成せずにdormantな状態が存在する.5)第9染色体に異常を持つ細胞はそれ自体では腫瘍形成に至らなくとも, 尿路内を播種又は上皮内進展する能力をもっている

One of the most important features of urothelial cancers of the bladder and upper urinary tract is metachronous and/or synchronous multifocal occurrence with high frequency. Since such multifocal recurrent tumors are derived from a common transformed cell, the chronological tracing of genetic alterations in such multifocal tumors may reveal the precise timing and role of genetic alterations in urothelial carcinogenesis. In this study, we tested the presence of microsatellite alterations in synchronous and/or metachronous multifocal urothelial cancers to examine the chronological genetic alterations for the presence of hierarchy of genetic alterations in urothelial cancer development. Genetic alterations at 20 microsatellite loci on 8 chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) were tested. Judging from the patterns of allelic deletion and microsatellite shifts, multifocal tumors in at least 21 (81%) of the 26 evaluable patients were considered to be derived from a single progenitor cell. In patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed at significantly lower frequencies on chromosome 9 compared with those on the other chromosomes tested. The heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. The data strengthens the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of urothelial cancers.