Chromosomal translocations among the healthy human population: implications in oncogenesis

Abstract

Chromosomal translocations are characteristic features of many cancers, especially lymphoma and leukemia. However, recent reports suggest that many chromosomal translocations can be found in healthy individuals, although the significance of this observation is still not clear. In this review, we summarize recent studies on chromosomal translocations in healthy individuals carried out in different geographical areas of the world and discuss the relevance of the observation with respect to oncogenesis.

Fig. 1

Chromosomal translocations resulting in juxtaposition of promoter/enhancer elements to oncogenes or chimeric fusion proteins. In hematological cancers, like leukemia and lymphoma, translocations can result in the juxtaposition of the coding region of a gene (gene A) to enhancer/promoter elements of another gene (gene B) (a). This results in the enhanced expression of the gene A under the influence of either the enhancer or alternative promoters. Alternatively, translocations can also result in the formation of a fusion/chimeric protein, which may have a novel or enhanced function (b). For example, upon translocation, gene A can join with gene B, resulting in a fusion product. Altogether, these alterations can lead to changes in the cellular physiology and morphology, thereby resulting in malignant transformation

Fig. 2

Models for transformation of a normal cell into cancer cell. a Hematopoietic stem cells can acquire chromosomal translocation as a primary hit and these cells can either differentiate or be maintained in stem cell compartments over long periods of time. The replicating, differentiating cells (leukemic stem cells) can then acquire secondary mutations over a period of time and develop into cancerous cells. b Alternatively, committed progenitors cells might undergo cellular reprogramming in order to get converted into stem cell-like cells, which upon acquiring secondary hits could become like cancer stem cells, responsible for the generation of the tumor over a period of time

Fig. 3

Model of initiation and progression of t(14;18)-bearing cell into follicular lymphoma. The pre-B cells, in the bone marrow, undergoing V(D)J recombination could develop the t(14;18) translocation and generate t(14;18)⁺ immature B cells. These cells upon antigen presentation in the germinal center undergo somatic hypermutation and class switch recombination, further acquiring possibly pathogenic mutations and could get selected upon antigenic stimulation. Such cells may evade apoptosis due to overexpression of the BCL2 protein and may be released in circulation or homed into undefined niches. These cells, which are more follicular lymphoma-like, now act as intermediates and may accumulate secondary aberrations in order to develop into the lymphoma