Hellman Asaf, Zlotorynski Eitan, Scherer Stephen W, Cheung Joseph, Vincent John B, Smith David I, Trakhtenbrot Luba, Kerem Batsheva
Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem 91904, Israel.
Cancer Cell. 2002 Feb;1(1):89-97. doi: 10.1016/s1535-6108(02)00017-x.
Oncogene amplification is an important process in human tumorigenesis, but its underlying mechanism is currently unknown. Cytogenetic analysis indicates that amplification of drug-selected genes in rodent cells is driven by recurrent breaks within chromosomal common fragile sites (CFSs), via the breakage-fusion-bridge (BFB) mechanism. Here we show that BFB cycles drive the intrachromosomal amplification of the MET oncogene in a human gastric carcinoma. Our molecular evidence includes a "ladder-like" structure and inverted repeat organization of the MET amplicons. Furthermore, we show that the breakpoints, setting the centromeric amplicon boundaries, are within the CFS FRA7G region. Upon replication stress, this region showed perturbed chromatin organization, predisposing it to breakage. Thus, in vivo induction of CFSs can play an important role in human oncogenesis.
癌基因扩增是人类肿瘤发生过程中的一个重要过程，但其潜在机制目前尚不清楚。细胞遗传学分析表明，啮齿动物细胞中药物选择基因的扩增是由染色体常见脆弱位点（CFS）内的反复断裂驱动的，通过断裂-融合-桥（BFB）机制。在这里，我们表明BFB循环驱动人胃癌中MET癌基因的染色体内扩增。我们的分子证据包括MET扩增子的“梯状”结构和反向重复组织。此外，我们表明，设定着丝粒扩增子边界的断点位于CFS FRA7G区域内。在复制应激时，该区域显示出染色质组织紊乱，使其易于断裂。因此，CFS的体内诱导在人类肿瘤发生中可能起重要作用。
