Souza R F, Yin J, Smolinski K N, Zou T T, Wang S, Shi Y Q, Rhyu M G, Cottrell J, Abraham J M, Biden K, Simms L, Leggett B, Bova G S, Frank T, Powell S M, Sugimura H, Young J, Harpaz N, Shimizu K, Matsubara N, Meltzer S J
Department of Medicine, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, 21201-1595, USA.
Cancer Res. 1997 Jun 15;57(12):2350-3.
The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.
E2F转录因子家族可反式激活促进细胞周期从G1期向S期过渡的基因。视网膜母细胞瘤（Rb）蛋白家族成员可与E2F结合并抑制其功能。E2F家族中的E2F-4，在体外转染至未转化细胞时可发挥癌基因功能。另一方面，纯合缺失正常E2F-1基因的小鼠会发生癌症，这与此基因的肿瘤抑制作用一致。因此，E2F的确切功能尚不清楚；此外，该基因在原发性人类肿瘤发生中的直接作用尚未得到证实。我们因此研究了16例原发性胃腺癌、12例溃疡性结肠炎相关肿瘤、46例散发性结直肠癌、9例子宫内膜癌和3例前列腺癌中E2F-4编码区的突变情况。我们将研究局限于E2F-4内的丝氨酸重复序列，理由是该区域在基因不稳定的肿瘤（复制错误阳性，即RER+）中可能会发生改变。除15例RER-散发性结直肠癌组成的对照组外，所有肿瘤均为RER+。使用位于丝氨酸三核苷酸（AGC）重复序列两侧的引物进行掺入[32P]dCTP的PCR。59例胃肠道肿瘤中有22例（37%）存在E2F-4突变；其中包括16例胃肿瘤中的5例（31%）、12例溃疡性结肠炎相关肿瘤中的4例（33%，包括1例发育异常病变）以及31例散发性结直肠癌中的13例（42%）。在任何子宫内膜、前列腺或RER-结直肠癌肿瘤中均未发现突变。值得注意的是，3例出现纯合突变，7例信息充分的患者中有2例在其肿瘤中显示一个E2F-4等位基因缺失。此外，对RER+散发性结直肠癌肿瘤的N-钙黏蛋白和β-连环蛋白基因内的三核苷酸重复序列进行了评估；未发现这些基因的肿瘤突变。这些数据表明，E2F-4是这些肿瘤中DNA修复缺陷的一个靶点。
