Causes of oncogenic chromosomal translocation

Abstract

Non-random chromosomal translocations are frequently associated with a variety of cancers, particularly hematologic malignancies and childhood sarcomas. In addition to their diagnostic utility, chromosomal translocations are increasingly being used in the clinic to guide therapeutic decisions. However, the mechanisms that cause these translocations remain poorly understood. Illegitimate V(D)J recombination, class switch recombination, homologous recombination, non-homologous end-joining and genome fragile sites all have potential roles in the production of non-random chromosomal translocations. In addition, mutations in DNA-repair pathways have been implicated in the production of chromosomal translocations in humans, mice and yeast. Although initially surprising, the identification of these same oncogenic chromosomal translocations in peripheral blood from healthy individuals strongly suggests that the translocation is not sufficient to induce malignant transformation, and that complementary mutations are required to produce a frank malignancy.

Figure 1. Spectral karyotype analysis of malignant cells

A. Spectral karyotype from a patient with CML, showing a pseudodiploid karyotype with a t(9;22) translocation as the only detectable anomaly. B. Spectral karyotype of a bladder carcinoma, showing numerous numerical and structural chromosomal anomalies. (Both karyotypes courtesy of Drs. Thomas Ried and Hesed Padilla-Nash, NIH, NCI, Bethesda, MD.)

Figure 2. Molecular consequences of chromosomal translocation

A. Production of a chimeric fusion gene by chromosomal translocation. In this example, the translocation breakpoints occur between exons 13 and 14 of BCR, and exons 1 and 2 of ABL. Two reciprocal fusion genes are formed, with exon 13 of BCR fused to exon 2 of ABL (BCR-ABL fusion), and exon 1 of ABL fused to exon 14 of BCR (ABL-BCR fusion). One of the two reciprocal transcripts is often not expressed. Exons 2–12 and 15–22 of BCR, and exons 3–10 of ABL are not shown for the sake of clarity. B. Mis-expression of a normal gene. Either 5′ or 3′ regulatory sequences (for example, 5′ SIL regulatory sequences or 3′ TCRD enhancer sequences respectively) can be fused to the coding sequence of a growth-regulating gene such as SCL. SCL expression is now governed by the regulatory sequences of the translocation partner (Either SIL or TCRD in these examples). SCL exons 1–6 are shown..

Figure 3. Chromosomal translocation mediated via V(D)J recombination or class switch recombination (CSR)

A. In the germline TCRD, numerous V (variable), D (diversity), and J (joining) segments are dispersed over hundreds of kb. Each discrete V, D, or J segment is flanked by a heptamer-nonamer recombination signal sequence. A single C (constant) segment is present, as is a 3′ enhancer (E). Normal V(D)J recombination occurs through reconfiguration of the genomic DNA, with V, D, and J segments becoming spliced together as shown. A cryptic recombination signal sequence within the SCL locus can be recognized by the V(D)J recombinase complex, leading to an SCL-TCRD translocation. A fusion mRNA is formed between SCL (in the 3′untranslated region) and TCRD; SCL expression is now governed by the TCRD enhancer (Eδ). Although TCRD and SCL are shown in this example, translocations involving all antigen receptor loci (except TCRG) have been reported. B. Prior to CSR, IgM is produced as the VDJ segment of the mRNA transcript splices to Cμ. The recombination is mediated via switch (S) regions 5′ of the C regions. The μ and γ subscripts designate immunoglobulin classes. Following CSR, IgG is produced, as the VDJ segment of the mRNA transcript splices to Cγ1. An IGH-MMSET translocation is caused when the switch recombination occurs between a region within the MMSET gene and the Sμ region. MMSET expression is now governed by the immunoglobulin heavy chain enhancer (Eμ). Class switch recombination occurs only at the IGH locus and not at other antigen receptor loci. MMSET is shown as an example, but many other genes have been shown to be fused to the IGH locus via CSR.