Cytogenomics of cancers: from chromosome to sequence

Abstract

The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the "cytogenetic uniqueness" of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level.

Figure 1

Virtual cloning of 8q24 in Burkitt lymphoma showing MYC region breakpoints (modified from Toujani et al., 2009). A) In BL84 and Ly 47 cell lines, characterized by a t(8;22)(q24;q11), the der(8)t(8;22) region harboring the MYC locus was duplicated. For example on BL84, the chromosome 8 (labeled in green) appeared trisomic from pter to 8q24.2, 129.15 Megabases (BL84 partial RHG‐banding), then its ratio on aCGH appeared normal (BL84 Partial profiling aCGH), corresponding to the normal chromosome 8 and to the distal part of the chromosome 8 translocated to the der(22)(BL84 partial RHG‐banding). The breakpoint was observed distal to MYC as expected and is mapped to PVT1, between mir‐1205 and mir‐1206 (Toujani et al., 2009). The chromosome 22 (labeled in blue) from the centromere to the long arm telomere is first non modified. B) Then a complete loss of IGL (immunoglobulin light chain lambda) region is observed suggesting a physiological biallelic rearrangement of IGL, while the t(8;22) occurred during one of them. The IGK (immunoglobulin light chain kappa) and the IGH (immunoglobulin heavy chain) regions are also physiologically rearranged on a single allele (A & B). After this lost region, from 22q11 to qter, 21.58–49.05 Megabases, the chromosome 22 is trisomic.