Trisomy

The first nonrandom chromosome abnormality discovered in CLL was trisomy 12 (+12) (7), which is found in about one-third of those who show clonal abnormalities, i.e., about 17% of all patients (Fig. 1). Using FISH analysis, a somewhat higher percentage is achieved (8); about 24% of over 600 CLL patients studied showed evidence of trisomy 12 (for review, see ref. 9), whereas 16% had +12 in the German FISH study (10). Half of all patients with trisomy 12 have no additional abnormality, and although +12 may occasionally be seen in other tumors, it is most common in CLL, indicating a significant role in the pathophysiology of this disease. Interestingly, it is rare that trisomy 12 is found in all leukemia cells of an individual patient (11). The median percentage of CLL cells with trisomy 12 in a patient with such an abnormality is 50%, whether the analysis is performed by cytogenetics or by FISH, and some have +12 in only a few percent of their CLL cells.

The finding of a proportion of CLL cell samples with a normal karyotype is likely to represent a failure to activate leukemia cells and a subsequent analysis of normal cells. In others, small deletions and other submicroscopic changes are beyond detection by cytogenetics. A finding of cells with normal chromosomes coexisting with cells with clonal changes may indicate a clonal evolution, i.e., a secondary event occurring during the subsequent clonal development of the disease. However, if so, trisomy 12 should commonly appear in follow-up samples taken during the course of the disease, and in fact, this has not been the case in several cytogenetic studies in which repeated samples have been collected during progression of CLL (12). CLL cell clones are usually cytogenetically stable during progressive disease, which was recently confirmed using FISH techniques (13). This contrasts to chronic myelogeneous leukemia in blastic phase and follicular lymphoma in transformation, in which additional abnormalities are frequent. Additional abnormalities in CLL usually lead to an increased complexity of the karyotype in cells that already had multiple abnormalities at first analysis. These data indicate that chromosome abnormalities are not exclusively formed at a single transforming event but represent disturbed mitotic procedures during clonal evolution.

Trisomy 12 occurs more frequently together with some additional abnormalities, i.e.,+18,+19, or +3, whereas it is rare to find+12 together with del(13q) (11). This observation is likely to have biological significance, although the subcellular mechanisms remains totally unclear.

It is also of major interest that, although rare, structural abnormalities involving chromosome 12 in CLL almost always lead to an increased gene dosage through partial trisomies, i.e., duplications of parts of the chromosome, a finding that is distinctly uncommon with structural abnormalities involving other chromosome sites. One of our patients had CLL cells with five copies of the segment 12q13-15 when presenting with a very aggressive relapse (14) following autologous bone marrow transplantation. This and other cases suggest that genes of patho-physiological importance in CLL may be localized to this region. Trisomies are likely to occur through nondisjunction during mitosis. However, it is distinctly difficult to assess which mechanisms (and which genes) are involved in the survival and/or proliferation advantage of trisomic cells, and there are so far no valid data on the role of any trisomy in human tumors.

Trisomy 12 may be slightly more common in patients with the common pregerminal type of CLL with unmutated VH genes and poorer survival (15). It has also been associated with CLL having atypical morphology (16,17); we had already shown in 1985 that+12 was common in CLL with lymphoplasmacytoid cells (16), termed immunocytoma according to the Kiel classification.

Chromosomal Abnormalities

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Fig. 3. Unbalanced clonal chromosomal abnormalities in CLL according to chromosome arm. All breakpoints reported in CLL-patients in the Mitelman Database of Chromosome Abnormalities in Cancer 2001 (26). There is an uneven distribution, considering that the chromosomes are ordered according to size (#1 is the largest and #22 the smallest; X is large and Y is small).

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Fig. 3. Unbalanced clonal chromosomal abnormalities in CLL according to chromosome arm. All breakpoints reported in CLL-patients in the Mitelman Database of Chromosome Abnormalities in Cancer 2001 (26). There is an uneven distribution, considering that the chromosomes are ordered according to size (#1 is the largest and #22 the smallest; X is large and Y is small).

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Responses

  • Fatima
    Who likely is it to get trisomy 12?
    5 years ago

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