Bugert P, Wilhelm M, Kovacs G
Department of Urology, Ruprecht-Karls-University of Heidelberg, Germany.
Genes Chromosomes Cancer. 1997 Sep;20(1):9-15.
The FHIT gene locus at 3p14.2 covers about 500 kb, including the fragile site FRA3B and the constitutional t(3;8) breakpoint associated with the development of multiple renal cell carcinomas (RCC). A terminal deletion of the short arm of chromosome 3 with the most distal breakpoint in the FRA3B region is the characteristic genetic event in nonpapillary RCC. Since aberrant FHIT transcripts have been observed in gastrointestinal and other tumors, this gene has been suggested to function as a tumor suppressor. To evaluate the role of FHIT and the FRA3B region in the genetics of RCC, we analyzed FHIT expression by RT-PCR and performed microsatellite deletion mapping in the FHIT region. In addition to two cases from a t(3;8) family, only three out of 100 sporadic nonpapillary RCC showed a breakpoint within the FHIT region, whereas 94 tumors showed a deletion breakpoint proximal to the FHIT gene. FHIT transcripts of normal size were observed in 33 out of 34 tumors. Direct sequencing of eight PCR products revealed a normal FHIT sequence without mutations in the coding region. An established cell line from a renal cancer xenograft showed a smaller FHIT transcript. Sequence analysis revealed a mixture of several splicing variants of the FHIT gene. Since only three out of 100 sporadic nonpapillary RCC had a deletion breakpoint within the FRA3B/FHIT region, and since all but one renal cell tumor showed a normal FHIT transcript, we can exclude the involvement of the FHIT gene and the FRA3B region in the genetics of renal cell cancer.
位于3p14.2的FHIT基因座覆盖约500 kb，包括脆性位点FRA3B以及与多发性肾细胞癌（RCC）发生相关的染色体3短臂末端缺失断点。3号染色体短臂的末端缺失且断点最远端位于FRA3B区域是非乳头状RCC的特征性遗传事件。由于在胃肠道和其他肿瘤中已观察到异常的FHIT转录本，因此该基因被认为具有肿瘤抑制功能。为了评估FHIT和FRA3B区域在RCC遗传学中的作用，我们通过RT-PCR分析了FHIT的表达，并在FHIT区域进行了微卫星缺失图谱分析。除了来自一个t(3;8)家族的两例病例外，100例散发性非乳头状RCC中只有3例在FHIT区域内出现断点，而94例肿瘤的缺失断点位于FHIT基因近端。34例肿瘤中有33例观察到正常大小的FHIT转录本。对8个PCR产物进行直接测序，结果显示FHIT序列正常，编码区无突变。一株来自肾癌异种移植的已建立细胞系显示出较小的FHIT转录本。序列分析揭示了FHIT基因几种剪接变体的混合物。由于100例散发性非乳头状RCC中只有3例在FRA3B/FHIT区域内有缺失断点，并且除了1例肾细胞肿瘤外，所有肿瘤均显示正常的FHIT转录本，因此我们可以排除FHIT基因和FRA3B区域参与肾细胞癌的遗传学过程。
