Editorial [Targeting Genetic Instability in Cancer Cells (Guest Editor: Francesco Colotta)]

Cancer is caused by alterations in oncogenes, onco-suppressor genes and micro-RNA genes. These alterations are either genetic or epigenetic. Most genetic lesions of cancer are acquired, somatic events, although germ-line mutations can predispose to heritable or familial cancers. Cancer cells accumulate several genetic alterations, including chromosomal abnormalities and mutations in the nucleotide sequence of DNA. Using massively parallel sequencing technologies, tens of thousands of somatic mutations have been identified in cancer cell genome, hundreds of which in coding exons, along with tens of genomic rearrangements. Driver mutations, which provide a selectable fitness advantage to the cell and facilitate its clonal expansion, are estimated to be tens in different tumor types [1-5]. The most fundamental conclusion from DNA sequencing of cancer cells is that the cancer genome is composed of a larger number of infrequently mutated genes, each providing a small fitness advantage, and few commonly mutated genes. Despite the fact that a small number of these genes are mutated in a high proportion of cancers, the prevalence at which the majority are mutated within different tumors of the same cancer type is low. These results are not in accord with the classical paradigm, in which a small number of key genes, mutated in a linear temporal sequence, drive tumorigenesis [1-2]. DNA is continuously assaulted by a variety of endogenous (e.g. reactive radicals) and exogenous (e.g. radiations and carcinogens) agents that damage DNA. DNA lesions induced by these agents are normally repaired by an elaborated network of DNA repair pathways. Cancer cells frequently harbor defects in DNA repair pathways, leading to genetic instability that in turn, at least in part, contributes to generate the thousands of genetic alterations found in cancer cells. Attempts to uncover the molecular mechanisms underlying genetic instability in cancer cells have shown that there are at least two forms of genetic instability. Loss of mismatch repair (MMR) enzymes leads to random acquisition of somatic mutations throughout the genome (microsatellite instability, MIN) [6]. Defects of proteins involved in mitotic regulation lead to an increased rate of gain and/or loss of chromosome or portions thereof (chromosome instability, CIN) and aneuploidy [7]. Almost all cancer cells are genetically unstable [8] and chronic inflammation, as one of the most recognized risk factor for many cancers, induces, by a variety of direct and indirect mechanisms, genetic instability [9]. Genetic instability serves as the engine of tumor progression by random activation of oncogenes and inactivation of onco-suppressors. Genetic diversification induced by genetic instability bestows a growth advantage upon the cancer cells enabling them to clonally expand in a Darwinian somatic evolutionary process [10]. Acquisition of mutations in oncogenes and tumor suppressor genes, and in additional genes that normally function in maintaining genomic integrity, perpetuate genetic instability [8], which is itself subject to natural selection. Cells with too little genetic instability may die by insufficient adaptability whereas cells with too much genetic instability may die by genetic catastrophe. Genetic instability accounts for the most striking and clinically relevant features of cancer, namely genotypic and, as a consequence, phenotypic (and thus clinical) intertumor and intratumor heterogeneity of cancer cells, including acquisition of resistance to therapy. No two tumors are genetically and phenotipically alike and no single tumor is composed of genetically identical cells, with each cell having a unique mutational signature [11]. Although representing a specific and defining hallmark of cancer cells [8], genetic instability still remains an as-yet unexplored therapeutic target. The aim of this monographic issue entitled “Targeting genetic instability and anti-cancer strategy” is to collect contributions outlining the concept of targeting genetic instability (and molecular mechanisms thereof) as a truly innovative approach that specifically kills cancer cells with unstable genome while leaving unaffected normal, genetically stable normal cells with intact DNA repair systems.......