Chromosome gains and losses are broad alterations encompassing from few megabases (Mb) to hundred Mb or even whole chromosomes. As these duplications (3–8 copies) or simple deletions (of a unique copy, if the tumor is diploid) are quite large, they can affect hundred of genes and their significance to the carcinogenesis process is less understood. Although there is evidence suggesting chromosome selection preferences for aneuploid cells in certain cancer types and although changes in gene copy number are among the most frequent molecular events in human cancer genome, these kinds of aberrations do not seem to be targetable.

Certain tumors present genomic amplifications reflecting the acquisition of an increased number of DNA copies (from 8–10 to hundred sometimes) by multistep processes usually under positive selection. Often associated with late and/or aggressive stages of cancerous progress, these genomic inscreases can be infrachromosomal, and then called HSR for homogeneous staining region, or extrachromosomic as chromosomes double minute, which proposed mechanism is based on “bridge-fusion-break” iterations. Generally associated with the tumoral proliferation, the amplifications can be also found in initial phases in certain sarcomas. These addictions to a number of oncogenic drivers, leading to these amplifications, for example, genomically amplified MDM2 proteins, MET, HER2, and EGFR, are of particular interest because of pharmacological approaches which can directly target and inhibit the overexpressed protein (Fig. 3.3).

In a diploid organism, homozygous deletion refers to the loss of both alleles or a portion of both alleles from a genomic location. By extension, this physical loss affect both copies of the same gene or of the same chromosomal segment of a pair of homologous chromosomes. As multigenic deletion have severe consequences, and as the size of the deleted region is directly correlated to the number of the genes to be lost, the homozygous deletion is often small from few kilobases (Kb), which can arise within a tumor suppressor gene (intragenic deletion) to very few Mb affecting a small number of genes. Losses of PTEN, CDKN2A, RB1, or SMARCB1 are well-documented examples of genes inactivated by homozygous deletion. The double deleted region can be the intersection of two independent events, two large overlapping deletions (four distinct breakpoints), a small deletion associated to loss of the whole remaining homologous chromosome (only two different breakpoints on the remaining chromosome), and sometimes a small deletion with loss and reduplication of the chromosome also called somatic isodisomy.

Isodisomy is a very specific type of genomic aberration in which the two copies of the chromosome originate from the same chromosome (inherited from one parent) with resultant homozygosity at all gene loci on the considered chromosome. Most often, isodisomy concerns an entire chromosome when the homologous chromosome is lost, but it may also be limited to part of a chromosome (segmental isodisomy). The presence of isodisomy in a tumor genome can highlight a simple mechanism to obtain biallelic inactivation of a tumor suppressor gene which is already mutated or disrupted on one allele (Fig. 3.4).

As translocations directly affect a small number of genes, the role of many translocations in cancer causation has become much clearer over the years. These translocations can be within a chromosome (with the homologous chromosome or inversion inside the same chromosome). They can also occur between different chromosomes and in a nonreciprocal manner (often with loss of material) or can form ring chromosome.

In 1960, studying chronic myeloid leukemia, Nowell and Hungerford observed the first cytogenetic reorganization acquired and recurring: the Philadelphia chromosome. This recombination between chromosomes 9 and 22 leads to the translocation t(9;22)(q34;q11) (Nowell and Hungerford 1960).

These chromosome translocations can have two types of consequences:

Upregulation of the expression of a gene. In this case, the reorganization juxtaposes the strong elements of regulation of the promoter of one a gene (like IgH or TCR) near an oncogene and increases its transcription (Ott et al. 2013).

The identification of fusion transcripts not only supports the diagnosis but provides the basis for the development of novel therapeutic strategies aimed at blocking the aberrant activity of chimeric proteins. Molecular biology and, in particular, cytogenetic and qualitative and quantitative RT-PCR technologies allow with high efficiency and specificity the determination of specific fusion transcripts resulting from chromosomal translocations. In prostate cancer, the TMPRSS2-ERG fusion is found in ∼50 % of all tumors, making it the single most common genetic lesion of this disease (Gopalan et al. 2009). In Ewing’s sarcoma (EWSR1-ETS) or alveolar rhabdomyosarcomas (PAX3/7-FOXO1), the fusion detection as specific marker is mandatory for molecular diagnosis.

The recent discovery of a new kind of massive chromosomal rearrangement in different cancers, named “chromothripsis” (chromo for chromosome, thripsis for shattering), has questioned the established models for a progressive development of tumors. Indeed, this phenomenon, which is characterized by the shattering of one or a few chromosome segments followed by a random reassembly of the fragments generated, occurs during one unique cellular event. Diverse situations can cause chromothripsis (radiations, telomere erosion, abortive apoptosis, etc.), and two express “repair routes” are used by the cell to chaotically reorganize the chromosomal regions concerned: nonhomologous end joining and repair by replicative stress (Korbel and Campbell 2013; Zhang et al. 2013)

In their normal nonmutated state, GoF genes are called proto-oncogenes and are directly or indirectly involved in controlling the rate of cell growth and are implicated in the regulation of cell division. When altered by a genetic event, such as point mutation, translocation, or chromosome amplification, these cancer-promoting genes become then abnormally activated and named oncogenes.

Mutations affecting oncogenes are most often somatic, but germinal activating mutations have already been described (e.g. RET involved in multiple endocrine tumor type II and MET gene in hereditary papillary cancer of the kidney) (Santoro et al. 2002; Linehan et al. 2007).

The activation of GoF is dominant, the alteration of only one allele being sufficient to confer an oncogenic potential. The consequences of this activation can be seen at the expression level or at the DNA level of the targeted gene.