Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity
Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity
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DOI：
10.1158/1078-0432.ccr-06-2085
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发表时间：
2007-02-01
影响因子：
11.5
通讯作者：
Bertherat, Jerome
中科院分区：
文献类型：
--
作者：
Libe, Rossella;Groussin, Lionel;Bertherat, Jerome
目的：在肾上腺皮质癌中，17p13基因座的等位基因丢失[杂合性缺失(LOH)]是常见的(85%)。抑癌基因TP53位于17p13。实验设计：通过Southern blotting检测36例肾上腺皮质肿瘤中的TP53体细胞突变、基因内LOH(VNTR1标记物)和P53的过表达。结果：在33%的肾上腺皮质肿瘤中发现了TP53的突变，44%的肾上腺皮质肿瘤中存在VNTR1杂合性缺失，并且并不总是与TP53突变相关。只有TP53突变的肿瘤表现出较强的核免疫反应。突变型肿瘤体积明显大于野生型肿瘤(中位肿瘤重量：640比185g；P=0.02)，肿瘤进展较晚期(MacFarlane IV期；P=0.01)，无病生存期较短(P=0.03)。结论：仅有少数17p13缺失的肾上腺皮质肿瘤存在VNTR1 LOH或TP53突变，提示17p13缺失可能不是参与肾上腺皮质癌进展的唯一或主要抑癌基因。我们认为，17p13区域的遗传不稳定性发生在肾上腺皮质癌发生的早期，涉及位于该区域的各种基因。TP53可能只是其中之一，它的失活突变的发生与更具侵袭性的肿瘤的发展有关。
Purpose: Allelic losses [loss of heterozygosity (LOH)] at the 17p13 locus are frequent (85%) in adrenocortical cancers. The tumor suppressor gene TP53 is located at 17p13. The aim of the study was to determine the frequency of TP53 somatic inactivating mutations in adrenocortical tumors with 17p13 LOH and their clinico-biological correlations.Experimental Design: TP53 somatic mutations, intragenic LOH (VNTR1 marker), and p53 overexpression were studied in 36 adrenocortical tumors with 17p13 LOH determined by Southern blot.Results: TP53 mutations were detected in 33% of the tumors, and VNTR1 LOH was present in 44% of the cases and did not always correlate with the presence of a TP53 mutation. Only the TP53-mutant tumors exhibit a strong nuclear immunoreactivity. TP53-mutant tumors were significantly larger than wild-type TP53 tumors (median tumor weight: 640 versus 185 g; P = 0.02), were associated with a more advanced stage of tumor progression (MacFarlane stage IV; P = 0.01), and had a shorter disease-free survival (P = 0.03).Conclusions: The finding that only a minority of adrenocortical tumors with 17p13 LOH had either a VNTR1 LOH or a TP53 mutation indicates that TP53 might not be the only or major tumor suppressor gene at 17p13 involved in adrenocortical cancer progression. We suggest that a genetic instability of the 17p13 region, occurring early in adrenocortical cancer development, involves various genes located in this region. TP53 might be only one of them, and its alteration by the occurrence of inactivating mutation is associated with the development of more aggressive tumors.