Detecting the presence of translocations

Some translocations are disease-specific

Follicular lymphoma is characterized by the t(14;18), which is found in almost 90% of cases. However, this translocation is found in other types of non-Hodgkin's lymphoma (NHL), so that the t(14;18) is not, in itself, diagnostic of one particular malignancy. Acute promyelocytic leukemia (AML M3) is characterized by a reciprocal translocation between chromosomes 15 and 17. This is found in the majority of cases but, unlike t(14;18), the t(15;17) is not found in any other neoplasm or in health and so serves as a diagnostic marker for this disease (although its absence does not exclude the diagnosis). Although t(9;22) is characteristic of CML, it is important to detect this in cases in which blastic transformation has occurred. In addition, t(9;22) occurs in a subset of patients with acute lymphoblastic leukemia (ALL) and in these cases is associated with a particularly poor prognosis. It is therefore important to identify these patients at diagnosis since their prognosis and treatment differ from those for other cases of ALL.

More recently a number of chromosomal translocations that were thought to be leukemia- or lymphoma-specific have been found in the blood of normal individuals when assessed by PCR amplification, including t(14;18), t(8;14), t(2;5),

Table 6.3 Detecting the presence of translocations. Standard cytogenetics

If the translocation alters the appearance of banded chromosomes using standard cytogenetic analysis.

Fluorescence in situ hybridization (FISH)

Using metaphase or interphase techniques.

Polymerase chain reaction

Requires the DNA on either side of the breakpoint to be sequenced to allow oligonucleotide primers to be constructed.

t(9;22), t(4;11), t(15;17) and t(12;21). The implication of this finding is that these rearrangements are not themselves sufficient for malignant transformation of cells, in keeping with a multi-hit hypothesis for tumor development.

Translocations may be used for detecting residual disease

Translocations serve as useful diagnostic disease markers at presentation for a variety of leukemias and lymphomas. For the detection of MRD, standard cytogenetic analysis for the detection of translocations is not sufficiently sensitive for follow-up but other techniques can be applied, including FISH and PCR. FISH techniques are constantly being improved (see Chapter 2) and may be of value for MRD detection. However, more sensitive MRD detection is possible using PCR in cases where the translocations are well characterized and DNA on either side of the breakpoints has been sequenced. MRD using the chromosomal translocations t(14;18) and t(9;22) and other translocations are described later.

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