Hino O, Kobayashi E, Hirayama Y, Kobayashi T, Kubo Y, Tsuchiya H, Kikuchi Y, Mitani H
Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Mol Carcinog. 1995 Sep;14(1):23-7. doi: 10.1002/mc.2940140106.
We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat. The homozygous mutant condition is lethal at around the 13th day of fetal life. In heterozygotes, RCs invariably develop in the first year of life. Histologically, RCs develop through multiple stages from early preneoplastic lesions (i.e., phenotypically altered tubules) to adenomas. The wild-type allele mutation has been found even in the earliest preneoplastic lesions, fitting Knudson's two-hit hypothesis and supporting the hypothesis that Tsc2 is a tumor suppressor gene. In this study, homozygous deletion of the Ink4 homologue on rat chromosome 5q was observed in 14 of 24 (58%) RC-derived cell lines. This may represent involvement of a second tumor suppressor gene, contributing to tumor progression. Considering previous results of studies of homozygous deletion of the Ifn alpha gene in five of 24 cases (21%) and the Ifn beta gene in one of 24 cases (4%), the order of the genes may be Ink4-Ifn alpha-Ifn beta. Microsatellite instability was not observed in 26 Eker rat tumors.
我们最近在大鼠10号染色体长臂上发现了结节性硬化基因（Tsc2）的种系突变，该基因是导致埃克大鼠肾癌（RC）的易感基因。纯合突变状态在胎儿期第13天左右致死。在杂合子中，肾癌在出生后第一年必然会发生。从组织学上看，肾癌从早期的癌前病变（即表型改变的肾小管）发展到腺瘤经历多个阶段。即使在最早的癌前病变中也发现了野生型等位基因突变，这符合Knudson的双击假说，并支持Tsc2是肿瘤抑制基因的假说。在本研究中，在24个（58%）源自肾癌的细胞系中，有14个观察到大鼠5号染色体长臂上Ink4同源物的纯合缺失。这可能代表第二个肿瘤抑制基因的参与，促进了肿瘤进展。考虑到先前的研究结果，24例中有5例（21%）存在Ifnα基因纯合缺失，24例中有1例（4%）存在Ifnβ基因纯合缺失，这些基因的顺序可能是Ink4-Ifnα-Ifnβ。在26个埃克大鼠肿瘤中未观察到微卫星不稳定性。
