Cancer chromosomal translocations

Imamura T, Kakam N, Hibi S, Morimoto A, Eukushima Y, ljuin 1, Hada S, Kitabayashi 1, Abe T, Imashuku S (2003) Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2 8)(p23 pll). Genes Chromosomes. Cancer 36 413 19... 

Figure 2. Chromosomal translocations leading the production of a MYST HAT fusion protein and cancer, (a) structure of different MYST HAT fusion proteins leading to cancer. Numbers indicate amino acid positions at break points, (b) Model for die consequences of EPCl-PCL fusion on chromatin function...

Enl is a translocation partner for MLL that is a common target for chromosomal translocations in human acute leukemia. Truncating mutations of hSNF5/INH are associated with aggressive pediatric cancer... 

As in cancer predisposing syndromes, these genetic alterations are sometimes carried in the germline. Among human tumours, heritable mutations are an exception. Most alterations are acquired in somatic life in the form of chromosomal translocations, deletions, inversions, amplifications or point mutations. Certain oncogenic viruses play important roles in a few human tumours. Examples are human papilloma-virus in cervical cancer and skin tumours, Ep-stein-Barr virus in nasopharyngeal carcinoma and Burkitt s lymphoma, and human T-cell leukaemia viruses (e.g. HTLV-I, HTLV-II) in T-cell leukaemia. 

Rabbitts, TH. Chromosomal translocations in human cancer (1994) Nature 372, 143-149... 

The hallmark and molecular characteristic of progression is karyotype instability. This is due to disruption of mitotic apparatus, alteration of telomere function, DNA hypomethylation, chromosome translocations and recombination, gene amplification, and gene transposition. There is also alteration of mismatch repair genes in some cancers. 

Chromosomal translocations are frequently associated with specific types of cancer. This is direct evidence that genetic abnormalities can lead to cancer. 

Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, Gjedde SB, Philip P, Hansen M, Larsen SO, Rorth M, Mouridsen H, Dombernowsky P. Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band Hq23 after therapy with 4-epi-doxorubicin and cisplatin or cyclophosphamide for breast cancer J Chn Oncol 1992 10(9) 1444-51. 

The concomitant occurrence of additional genetic aberrations and chromosomal translocations is common in hematological malignancies. The HAS oncogene is one of the most frequently mutated genes in cancer,and is mutated in up... 

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124—18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic Philadelphia chromosome translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome-positive cells. It is relatively, but not completely, selective for these cells. °°... 

FIGURE 132-1. Diagram of the chromosomal translocation that results in the Philadelphia chromosome. This abnormality is encountered in 90% to 95% of patients who have chronic myelogenous leukemia. (From Fishleder AK. Oncogenes and cancer clinical applications. Cleve Clin J Med 1990 57 721-726.)... 

A distinction is made between biomarkers and bioindicators because they can be used in quite different ways and for different purposes in a risk assessment context. As mentioned above, a biomarker is considered to be a surrogate marker of exposure or an early biological marker of effect (e.g., mutations in reporter genes, total chromosome alterations). In contrast, a biological marker of effect that is itself a key event along the pathway from a normal cell to a transformed one is described as a bioindicator (e.g., mutation in critical gene for cancer, cancer-specific chromosome translocation). Biomarkers can be used to inform the dose-response for tumors in a qualitative manner. Bioindicators can be used in a qualitative and quantitative way to inform tnmor dose-response curves. Use of these biomarkers and bioindicators can make it feasible to characterize a dose-response curve at exposure levels below those at which increases in tnmor frequency can be assessed. 

Another improvement for tests when the initial template is RNA rather than DNA is to have a single thermostable enzyme that can function both as a reverse transcriptase and as a DNA polymerase (M12). This would greatly simplify tests for RNA viruses, for bacterial targets that utilize ribosomal RNA targets, and for cancer tests such as for the hybrid mRNA associated with the BCR-ABL chromosomal translocation in chronic myeloid leukemia. 

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