Le Beau M M, Drabkin H, Glover T W, Gemmill R, Rassool F V, McKeithan T W, Smith D I
Section of Hematology/Oncology, University of Chicago, Illinois 60637, USA.
Genes Chromosomes Cancer. 1998 Apr;21(4):281-9. doi: 10.1002/(sici)1098-2264(199804)21:4<281::aid-gcc1>3.0.co;2-v.
The FRA3B at 3p14.2 is the most common of the constitutive aphidicolin-inducible fragile sites. Using independent approaches, four groups of investigators have cloned and characterized this fragile site. The results of these studies have revealed that the FRA3B differs from other heretofore cloned rare fragile sites. First, instability as manifested by chromosome breakage occurs over a large region of DNA, encompassing at least 500 kb. Second, sequence analysis has not revealed trinucleotide repeat motifs, characteristic of the rare fragile sites. In addition to containing the FRA3B, band 3p14 is also likely to contain a tumor suppressor gene, as evidenced by the presence of deletions, rearrangements, and allele loss in a variety of human tumors, including lung, renal, nasopharyngeal, cervical, and breast carcinomas. The recently cloned FHIT gene in 3p14.2 is a promising candidate tumor suppressor gene, since aberrant FHIT transcripts have been found in a significant proportion of cancer-derived cell lines and primary tumors of the digestive and respiratory tracts. Nonetheless, several lines of evidence garnered over the past year have called into question the role of FHIT as a classical tumor suppressor gene, and raised the question of whether its apparent involvement simply reflects its location within an unstable region of the genome. In the following study, we have summarized the evidence in support of FHIT as a tumor suppressor gene as well as evidence against such a role, and the experimental evidence needed to demonstrate that FHIT functions as a tumor suppressor gene in the pathogenesis of human tumors. The paradigm of FHIT emphasizes that confirming the role of a candidate tumor suppressor gene may prove difficult, particularly for those genes that are located in genetically unstable regions.
位于3p14.2的FRA3B是最常见的组成型 aphidicolin 诱导型脆性位点。四组研究人员采用独立的方法对该脆性位点进行了克隆和表征。这些研究结果表明，FRA3B与其他迄今克隆的罕见脆性位点不同。首先，由染色体断裂表现出的不稳定性发生在大片段DNA区域，至少涵盖500 kb。其次，序列分析未发现罕见脆性位点特有的三核苷酸重复基序。除了包含FRA3B外，3p14带也可能包含一个肿瘤抑制基因，这在包括肺癌、肾癌、鼻咽癌、宫颈癌和乳腺癌在内的多种人类肿瘤中出现的缺失、重排和等位基因丢失现象中得到了证实。最近在3p14.2克隆的FHIT基因是一个很有前景的候选肿瘤抑制基因，因为在相当比例的源自癌症的细胞系以及消化和呼吸道原发性肿瘤中发现了异常的FHIT转录本。尽管如此，过去一年收集的几条证据对FHIT作为经典肿瘤抑制基因的作用提出了质疑，并引发了其明显参与是否仅仅反映其在基因组不稳定区域内的位置这一问题。在以下研究中，我们总结了支持FHIT作为肿瘤抑制基因的证据以及反对这一作用的证据，以及证明FHIT在人类肿瘤发病机制中作为肿瘤抑制基因发挥作用所需的实验证据。FHIT的范例强调，证实候选肿瘤抑制基因的作用可能很困难，特别是对于那些位于基因不稳定区域的基因。
