Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21)
Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21)
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DOI：
10.1093/hmg/11.6.641
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发表时间：
2002-03-15
影响因子：
3.5
通讯作者：
van Kessel, AG
中科院分区：
文献类型：
--
作者：
Bodmer, D;Eleveld, M;van Kessel, AG
以前，我们描述了一个家庭与一个显着增加的易感性肾细胞癌共分离的t（2;3）（q35;q21）染色体易位。在分子水平上分析了来自不同家族成员的几种透明细胞型原发性肿瘤。此外，在大多数分析的肿瘤中观察到不同的体细胞Von Hippel Lindau（VHL）基因突变，即使在同一患者中也是如此。基于这些结果，提出了一种多步骤肿瘤发生模型，其中衍生染色体3的（非分离）丢失代表早期事件，VHL基因的体细胞突变代表与肿瘤进展相关的晚期事件。然而，最近，我们注意到这两个异常在我们测试的至少一个早期肿瘤样本中不存在。在另一个肾细胞癌和t（3;6）（q12;q15）的家族中也得到了类似的结果，因此表明在这两个致癌步骤之前可能有另一个遗传事件。我们推测，位于易位断裂点处或附近的基因的失调可能起作用。为了鉴定这些基因，构建了包含3q 21断裂点区域的详细物理图谱。通过随后的定位克隆工作，我们发现这个断点靶向一个迄今尚未鉴定的基因，命名为DIRC 2（在肾癌2中被破坏）。计算机预测的推定DIRC 2蛋白质显示出显着的同源性的主要促进超家族（MFS）的转运蛋白的不同成员。基于额外的DIRC 2表达和突变分析，我们提出，所观察到的基因破坏可能导致单倍不足，并通过这种机制，在肿瘤生长的发病。
Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth.