Trisomy 12 was the first recurring chromosome abnormality noted in CLL and was reported by Gahrton in 1980 (34). Standard metaphase G-banding or Q-banding identified trisomy 12 as the most frequent chromosomal abnormality in CLL, present in the leukemia cells of 10-20% of patients (35,36). However, when more sensitive techniques such as interphase FISH are applied (Fig.2), it is not the most frequent abnormality, but ranks second or third. Of note, a higher proportion (up to 35%) of CLL cases have trisomy 12 by FISH analysis than is noted by standard karyotyping methods, and it is commonly present in a subpopulation of leukemia cells (37-42).
Duplication of one chromosome 12 and retention of the second is the usual mechanism for trisomy (43,44). Localization studies indicate that 12q13-15 is the minimal duplication region needed for the expected clinical picture associated with trisomy 12 (45). Partial trisomy 12 may occur by a mechanism of translocation or duplication of 12q13-22 (45,46). A specific gene or genes associated with trisomy 12 has not been identified. One candidate gene that may be involved in leukemogenesis is the human homolog of the mouse double minute 2 (MDM2) gene, HDM2, located at 12q13-15 (47,48). The HDM2 gene is over-expressed in more than 30% of B-cell CLL cases (49). MDM2 protein binds and inactivates p53 by promoting proteosome-medi-ated p53 degradation (50,51).
Trisomy 12 was hypothesized to be a primary germline defect, occurring in CD34+ hematopoietic progenitor cells (52,53). However, subsequent studies failed to confirm this (54). Furthermore, sequential karyotype studies suggest that trisomy 12 may be involved in disease progression or clonal evolution rather than primary leukemogenesis (39,55,56). Trisomy 12 is most commonly noted in a subpopulation of leukemia cells, indicating that it may be a secondary event that occurs within an established leukemia clone (39,56-59). Furthermore, the proportion of leukemia cells carrying trisomy 12 can vary by anatomic location, being highest in lymph nodes, followed by bone marrow and blood (60,61). Trisomy 12 may occur singly or may be associated with complex karyotypic abnormalities (36,42,55). One study employing FISH analysis found that nearly half of the cases with 13q14 deletions had trisomy 12 (62). Multiple abnormalities combined with trisomy 12 carry a worse prognosis than trisomy 12 alone (1,63).
Patients who have trisomy 12 have a worse prognosis than those with a diploid karyotype or 13q deletion (1,35,36,63-65). In fact, univariable analysis indicates a shorter treatment-free interval and shorter overall survival in patients with trisomy 12 compared with the survival of
CEP12 probe (Vysis)
Fig. 2. Interphase FISH analysis for trisomy 12. FISH analysis was performed on blood mononuclear cells of a patient with B-cell CLL using a 12q probe (CEP12 probe [Vysis]). Cells displaying trisomy 12 (pink hybridization signals) are indicated in the figure. Cells with disomic and monosomic status are also noted for comparison. (Courtesy of Dr. Armand Glassman, Department of Hematopathology, U.T. M.D. Anderson Cancer Center, Houston, TX.)
patients with any other single chromosome abnormality (1). Other studies do not confirm this report (2,66,67). Trisomy 12 has been associated with several negative prognostic features such as atypical leukemia cell morphology (increased prolymphocytes), unmutated IgVH gene, high CD38 expression, and advanced and progressive disease (31,33,68-74). Trisomy 12 has also been associated with the presence of monoclonal paraprotein (35,36,68).
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