Kurahashi H, Takami K, Oue T, Kusafuka T, Okada A, Tawa A, Okada S, Nishisho I
Department of Medical Genetics, Osaka University Medical School, Japan.
Cancer Res. 1995 Nov 1;55(21):5007-11.
Familial adenomatous polyposis (FAP) is an inherited disorder caused by germline mutation of the adenomatous polyposis coli (APC) gene. Increased risk of hepatoblastoma (HBL) in FAP kindreds has been reported. To determine whether inactivation of the APC gene plays a role in development of HBL, 13 sporadic infantile hepatic tumors were analyzed for genetic alterations in the APC gene. A PCR-mediated RNase protection analysis was performed to detect subtle genetic alterations in the mutation cluster region and in exons 3 and 4 of the APC gene. The results showed that a G to T transversion at the splice acceptor site of the intron 3-exon 4 junction had occurred in one HBL. Sequence analysis of normal tissue of the patient proved the mutation to be germinal. Southern blot analysis at the APC locus revealed that the tumor had lost the opposite allele and was isodisomic at this locus. RNA analysis indicated that the tumor contained only the small APC transcript, from which exon 4 was entirely absent. Since abnormal splicing causes termination due to frameshift, it was hypothesized that only the truncated APC protein was expressed in this tumor. These findings suggest that inactivation of the APC gene is closely related to tumorigenesis of HBLs in FAP patients.
家族性腺瘤性息肉病（FAP）是一种由腺瘤性息肉病 coli（APC）基因的种系突变引起的遗传性疾病。已有报道称 FAP 家族中肝母细胞瘤（HBL）的风险增加。为了确定 APC 基因的失活是否在 HBL 的发生中起作用，对 13 例散发性婴儿肝脏肿瘤进行了 APC 基因的遗传改变分析。进行了 PCR 介导的 RNase 保护分析，以检测 APC 基因突变簇区域以及第 3 和第 4 外显子中的细微遗传改变。结果显示，在一个 HBL 中，第 3 内含子-第 4 外显子连接处的剪接受体位点发生了 G 到 T 的颠换。对该患者正常组织的序列分析证明该突变是胚系的。APC 基因座的 Southern 印迹分析显示，肿瘤丢失了另一个等位基因，并且在该基因座是等二体的。RNA 分析表明，肿瘤仅包含小的 APC 转录本，其中完全没有第 4 外显子。由于异常剪接由于移码而导致终止，因此推测该肿瘤中仅表达截短的 APC 蛋白。这些发现表明，APC 基因的失活与 FAP 患者中 HBL 的肿瘤发生密切相关。
