Acquisition Order of Ras and p53 Gene Alterations Defines Distinct Adrenocortical Tumor Phenotypes

Abstract

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.

Generation of autochthonous mouse models of clear cell renal cell carcinoma: mouse models of renal cell carcinoma

“…Other ways to improve the outcome might be controlling different gene alterations in chronological order rather than simultaneously, for example, deleting Vhl first and then other genes after an interval. This suggestion is based on an observation that the tumor phenotype is directly shaped by the order of acquisition of genetic alterations 84 and that the order of genetic mutations influences the clonal evolution of cancer 85 . Altering genes in order rather than simultaneously might better resemble the natural process of tumorigenesis, although this manipulation would increase the difficulty of experiments.…”

Effects of ordered mutations on dynamics in signaling networks

“…For example, the double mutation in the order of TP53 and NOTCH, which are representative tumorsuppressor and oncogenes, respectively, was frequently observed in early stage of esophageal carcinoma patients [53], whereas the reverse-ordered mutation is likely to lead to a metastasis progression in mouse experiments [63,64]. It was also shown that alteration of RAS, which is another oncogene, before loss of P53 formed a malignant tumor with metastatic behavior, but the reverseordered mutation resulted in benign tumors [2,65].…”

Order Matters: The Order of Somatic Mutations Influences Cancer Evolution

“…The first suggestion that the temporal sequence of two mutations might impact tumorigensis was in a mouse model of adrenocortical tumors[38]. When oncogenic Ras was over-expressed before loss of p53, highly malignant tumors with metastatic properties were formed in contrast to the benign tumors that resulted from the reverse mutational order.…”