Yeung R S, Xiao G H, Jin F, Lee W C, Testa J R, Knudson A G
Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA 19111.
Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11413-6. doi: 10.1073/pnas.91.24.11413.
Genetic predisposition to neoplasia often involves tumor suppressor genes. One such model of hereditary renal carcinoma was described in the rat by Eker. These tumors share morphologic similarities with human renal cancer. Linkage analysis localized the inherited mutation to rat chromosome band 10q12. This region is syntenic with human chromosome band 16p13.3, the site of the tuberous sclerosis 2 (TSC2) gene. A specific rearrangement of the rat homologue of TSC2 was found to cosegregate with carriers of the predisposing mutation. Tumors with or without loss of heterozygosity expressed only the mutant allele, consistent with the two-hit hypothesis. This mutation gave rise to an aberrant transcript that deletes the 3' end normally containing a region of homology with the catalytic domain of rap1GAP.
肿瘤形成的遗传易感性通常涉及肿瘤抑制基因。一种遗传性肾癌的模型由埃克在大鼠中描述。这些肿瘤在形态学上与人类肾癌相似。连锁分析将遗传性突变定位到大鼠染色体带10q12。该区域与人类染色体带16p13.3同源，后者是结节性硬化症2（TSC2）基因的位点。发现TSC2大鼠同源物的特定重排与易感性突变携带者共分离。有或没有杂合性缺失的肿瘤仅表达突变等位基因，这与双打击假说是一致的。这种突变产生了一种异常转录本，该转录本缺失了通常与rap1GAP催化结构域具有同源区域的3'末端。
