来自法国国立健康与医学研究学院的研究人员5月10日表示，对正常的肾上腺皮质细胞以不同的顺序导入Ras和p53突变体基因，会产生出不同的肾上腺皮质癌的表型，即遗传变异获得顺序不同会表现出不同的肿瘤表型。
肾上腺皮质癌(ACC)是一种罕见的内分泌肿瘤，往往预后极差，与此相反，肾上腺皮质瘤为良性肿瘤，在人群中较为常见。
肾上腺皮质瘤是否为一个独立的肿瘤实体，亦或是肾上腺皮质癌发展的一个阶段性表现，目前仍不明确。
为此，他们创建了一个预示肿瘤发展的老鼠模型，在这种模型中，正常的肾上腺皮质细胞被导入了肾上腺皮质瘤中的突变基因。
癌基因Ras等位基因(H-RasG12V)及p53突变体（p53DD）能够扰乱p53信号通路而产生肿瘤，研究发现，以不同的顺序导入这两种基因，会在组织特征、致瘤性及转移行为表现出显著差异。
RasG12V及p53DD的成功表达会导致具有转移特性的高度恶性肿瘤，然而以相反的顺序导入后，促进发生的仅仅为良性肿瘤。
微阵列分析表明157个基因与癌症发展有关。对比于良性细胞群，在恶性肿瘤细胞群中，这些基因里有40个基因的表达上调，117个基因的表达下调。
研究人员Michal Thomas表示，这是第一次由实验观察结证明肾上腺皮质癌是由多级进程发展而来，而遗传变异的获得顺序直接影响了肿瘤的表型。（生物谷Deepblue编译）
doi: 10.1371/journal.pgen.1002700
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Acquisition Order of Ras and p53 Gene Alterations Defines Distinct Adrenocortical Tumor Phenotypes
Maryline Herbet, Aude Salomon, Jean-Jacques Feige, Michal Thomas.
Sporadic adrenocortical carcinomas (ACC) are rare endocrine neoplasms with a dismal prognosis. By contrast, benign tumors of the adrenal cortex are common in the general population. Whether benign tumors represent a separate entity or are in fact part of a process of tumor progression ultimately leading to an ACC is still an unresolved issue.To this end, we have developed a mouse model of tumor progression by successively transducing genes altered in adrenocortical tumors into normal adrenocortical cells.The introduction in different orders of the oncogenic allele of Ras (H-RasG12V) and the mutant p53DD that disrupts the p53 pathway yielded tumors displaying major differences in histological features, tumorigenicity, and metastatic behavior.Whereas the successive expression of RasG12V and p53DD led to highly malignant tumors with metastatic behavior, reminiscent of those formed after the simultaneous introduction of p53DD and RasG12V, the reverse sequence gave rise only to benign tumors.Microarray profiling revealed that 157 genes related to cancer development and progression were differentially expressed. Of these genes, 40 were up-regulated and 117 were down-regulated in malignant cell populations as compared with benign cell populations.This is the first evidence-based observation that ACC development follows a multistage progression and that the tumor phenotype is directly influenced by the order of acquisition of genetic alterations.
