Overexpression of DNA repair genes is associated with metastasis: a new hypothesis

Tumorigenesis is a multistep process, where it is believed that the transformation of normal cells into tumoral cells needs a succession of genetic and epigenetic changes, such as point mutations, chromosomal rearrangements, and changes in gene expression level. All these modifications are supposed to confer a selective advantage and to generate highly malignant cancer cells. Until recently, the same selection procedure of rare cells in the tumour mass was believed to be necessary for the metastatic process. Using gene expression profiling, several recent publications report that a gene expression signature could discriminate between primary tumours with high metastatic potentiality and poor clinical outcome, and primary tumours that are not going to metastasize. Analysis of the biological pathways associated with metastatic potential points to cell adhesion, angiogenesis, cell cycle regulation, initiation of DNA synthesis, and DNA repair. Analysing human primary malignant melanoma and various biological processes, we have shown that the overexpression of DNA repair pathways, particularly those involved in double-stand break repair and surveillance of the DNA replication forks, is associated with metastasis and poor patient survival [V. Winnepenninckx, V. Lazar, S. Michiels, P. Dessen, M. Stas, S.R. Alonso, M.F. Avril, P.L. Ortiz Romero, T. Robert, O. Balacescu, A.M. Eggermont, G. Lenoir, A. Sarasin, T. Tursz, J.J. van den Oord, A. Spatz, Gene expression profiling of primary cutaneous melanoma and clinical outcome, J. Natl. Cancer Inst. 98 (2006) 472-482]. These results, also found by analysing other types of human tumours, such as breast or bladder cancers, would clearly explain the high resistance of metastasis towards chemo- and radiotherapies. Our hypothesis is that genetic instability is absolutely necessary to go from normal cells to tumoral cells, but one needs some type of genetic stabilization, which can be obtained by overexpressing specific DNA repair genes, in order to produce primary tumour cells that are genetically stable enough to be able to invade and give rise to distant metastasis.