Trisomy

Trisomy 12 is by far the most frequent numerical chromosome abnormality in CLL. By means of restriction fragment length polymorphism studies, the additional chromosome 12 has been shown to derive from duplication of one chromosome 12 with retention of the other homologue rather than from triplication of a single homologue.22 The incidence of trisomy 12 in studies which have used both cytogenetic and interphase FISH analysis is shown in Table 6-2. The wide variation in incidence may in part reflect the extent to which studies include patients with atypical lymphocyte morphology, which, as discussed later, is strongly associated with trisomy 12.

The genetic consequence of trisomy 12 is unknown. Clues to the identity of the key gene or genes on chromosome 12 may come from the investigation of rare cases with translocations, duplications, or genomic amplifications involving chromosome 12. Two cases in which CLL had transformed to diffuse large-cell lymphoma were shown to have translocations involving 12p13 and 12q13, respectively. In the first case there was disruption of the cyclin D2 promoter.23 In the second the translocation occurred within the HMGI-C gene which encodes a high-mobility group protein known to be overexpressed in a variety of malignancies.24 Dysregulation of the chondroitin 4-0-sulfotransferase 1 gene has been reported in a single case of CLL with t(12;14)(q23; q32).25 In a study of duplications result-

D13S319 D13S25 _i_l_

Kalachikov et al 1997

Bouyge-Morcau et al 1997

— Stilgenbauer et al 1998

Figure 6-2. The solid bars indicate the minimum regions of genetic loss detected by FISH, microsatellite, or Southern analysis.

ing in partial trisomy 12 in patients with low-grade B-cell malignancies, a duplicated region between q13 and q22 was identified in patients with CLL.26 This region includes the MDM2 gene, the possible significance of which in CLL is discussed below.

Patients with hereditary papillary renal carcinoma have germ-line mutations of the MET oncogene on chromosome 7q31, frequently accompanied by trisomy 7. The duplicated chromosome 7 always carries the MET mutation. If trisomy 12 in CLL results in a gene dosage effect, the gene that is implicated may also be abnormal.27

DELETION OF 11q

Using a panel of YAC probes spanning 11q14 to q23, Stilgenbauer et al.28 investigated 38 patients with CLL who had cytogenetic deletions of chromosome 11q. A commonly deleted region of between 2 and 3 Mb at 11q22.3 to q23.1 was identified. In two additional cases with 11q translocations, the translocation breakpoints were localized to the commonly deleted region. In a subsequent larger interphase FISH study, 43 of 214 patients were found to have heterozygous loss of a YAC within the minimally deleted region.29 This high incidence of loss contrasts with previous cytogenetic studies in which 11q22

Table 6-2. Incidence of Trisomy 12 in Chronic Lymphocytic Leukemia

Study

Cytogenetics (%)

+ 12 by FISH (%)

Perez-Losada117

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