Advances in Understanding Genetic Changes in Cancer Impact on Diagnosis and Treatment Decisions in the 1990s (1992) / Chapter Skim
Currently Skimming:
3. Hematologic Cancer
3. Hematologic Cancer
Pages 25-44
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 25... ...
For these reasons, discussion of genetic changes in hematologic cancers is addressed on a disease-by-disease basis, whereas discussion of solid tumors is organized around certain general major issues in the genetics of solid tumors and a number of key alterations found among selected solid neoplasms. Table 2-1 provides an overview of the utility of a number of techniques in genetic testing of both hematologic cancers and solid tumors.
|
From page 26... ...
In some patients, blast crisis is presaged by a prodromal phase of disease acceleration. The only curative therapy for CML is bone marrow transplant, which has a good outcome when performed during the stable phase, but a poor outcome in patients in blast crisis.
|
From page 27... ...
(q35;pl3) Non-Hodgkin's lymphoma B Chronic lymphocytic leukemia RBTN1 TCRD TCL2b TCRD MYC TCRA IGH TCRA TCL1 TCRA TCL3a TCRD TCLS TCRD TCRB SUP-T3C TCRB TAN1 TCRG TCRG TCRB t(8; 14)
|
From page 28... ...
Experimental studies and the analysis of samples from patients have shown that the BCR sequence increases tyrosine kinase enzyme activity associated with ABL (281. Although the precise mechanism is unknown, it is clear that this unique form of ABL serves as a major factor in the transformation of hematopoietic cells (29~.
|
From page 29... ...
By using probes that span this region, most rearrangements involving BCR can be detected by Southern blot analysis. In one recent analysis of 68 patients with CML, use of two probes and several different restriction enzymes led to detection of BCR rearrangement in 61 of 61 Phi+ cases and 3 of 7 Phi- cases (32~.
|
From page 30... ...
Rearrangements involving BCR can also be directly visualized in interphase cells by in situ hybridization using probes for ABL and BCR together (34) , or by staining concomitantly with two BCR probes that flank the breakpoint region (Figure 2-11.
|
From page 31... ...
In one study following 27 patients with stable phase CML, 6 of the 8 patients who progressed demonstrated hypermethylation prior to transformation, with a median lead time of six months before the appearance of clinical disease acceleration (451. This approach shows promise, but it does not appear to be a 100% sensitive predictor of disease progression and needs further evaluation.
|
From page 32... ...
Prognosis is dependent upon clinical characteristics, such as patient age, peripheral white blood cell count, the immunophenotype of the tumor cells, and the presence of certain tumor-specific genetic lesions. Each of these prognostic factors tends to correlate with the others to varying degrees.
|
From page 33... ...
Identification of breakpoint sequences will permit detection by PCR, Southern blotting (69)
|
From page 34... ...
In some cases, TCL5 rearranges with the ~ T cell receptor locus on chromosome 14. The breakpoints are readily detected by Southern blot analysis and may be homogeneous enough for consistent detection by PCR as well.
|
From page 35... ...
It is possible that sensitive techniques of tumor detection would permit more accurate assessment of residual disease following treatment or of the kinetics of response during therapy, thereby allowing some patients to receive shorter courses and perhaps identifying patients for whom early bone marrow transplant is indicated. In those patients who do receive transplants, detection of residual disease post-transplant may identify a patient population that re
|
From page 36... ...
Unlike ALL, many of these chromosomal abnormalities tend to correlate well with tumor phenotype. Subclassification of AML based on standard morphologic criteria can, however, be difficult, and confirmation of AML subtype by genetic testing is likely to aid assignment of prognosis and therapies in many cases.
|
From page 37... ...
by Southern blotting using a combination of probes directed against RARA and MYL in 26 out of 26 cases of APL, and this may become the technique of choice for detecting this rearrangement. In situ hybridization may also prove useful, as well as PCR directed against the chimeric transcript.
|
From page 38... ...
In the case of APL, patient response to RA therapy appears to be correlated with the presence of the t(15;171. Finally, in principle, the unique DNA sequences generated by each of the translocations specific for AML are potential targets for approaches aimed at detection of minimal residual disease.
|
From page 39... ...
Both recombinational and junctional diversity contribute to the overall diversity of antigen receptors. In any particular lymphocyte, the configuration of DNA in a rearranged antigen receptor locus appears, for the most part, to be fixed throughout the life of the lymphocyte and its progeny; this is also true of neoplasms derived from transformed lymphocytes.
|
From page 40... ...
Diagram of hypothetical rearrangement in the immunoglobulin heavy chain gene. The relative positions of germline V,D,J, and C region segments are shown in the top line; the configuration of V,D,J, and C segments resulting from a rearrangement is shown in the bottom line.
|
From page 41... ...
The method most commonly employed for assessing the issue of clonality in such cases is Southern blot analysis using probes specific for antigen receptor genes (1101. Polyclonal proliferations contain many different antigen receptor gene rearrangements, each with its own configuration of rearranged segments.
|
From page 42... ...
, whereas rearrangements involving an immunoglobulin switch region are typically seen in sporadic cases of non-African Burkitt's lymphoma (74,115~. As in B cell ALL, due to the variability in the position of the breakpoints in MYC and in the immunoglobulin genes, detection of the rearrangement by Southern blotting and PCR is problematic, and cytogenetic analysis is currently the only reliable way of detecting these translocations.
|
From page 43... ...
Many other translocations have been described in a few cases of lymphoma. As a rule of thumb, those cases with B cell phenotype tend to have a rearrangement that involves one of the immunoglobulin genes, and those with T cell phenotype have rearrangements involving T cell receptor genes.
|
From page 44... ...
Some data also suggest that the presence of additional karyotypic abnormalities, particularly structural changes involving chromosome 17, identify patients with follicular lymphoma who have a poor prognosis (118,137,1381. More data are needed to corroborate this finding.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.