CYTOGENETIC AND MOLECULAR CYTOGENETIC ANALYSIS OF B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA - SPECIFIC CHROMOSOME-ABERRATIONS IDENTIFY PROGNOSTICSUBGROUPS OF PATIENTS AND POINT TO LOCI OF CANDIDATE GENES

The most frequent chromosome aberrations in B cell chronic lymphocytic leukemia (B-CLL) detected by conventional chromosome banding analysis are trisomy 12 followed by structural abnormalities of the long arms of chromosomes 13, 14, and 11. Complex karyotypes, trisomy 12, and a ' 14q+' abnormality have been associated with inferior prognosis, wherea s aberrations of 13q have been found in patients with a favorable outc ome. However, the cytogenetic analysis of B-CLL by conventional bandin g techniques has remained a difficult task mainly due to the low in vi tro mitotic activity of the tumor cells. Although B cell mitogens are used for cell culture, clonal chromosome aberrations are detected in o nly half of the B-CLL tumors. 'Interphase cytogenetics' by means of fl uorescence in situ hybridization (FISH) circumvents this problem, beca use there is no need to induce the malignant cells to proliferate in v itro. Numerical and structural chromosome aberrations can be detected in non-dividing interphase cells as well as in metaphase spreads. By F ISH, the most common chromosome abnormalities are deletions of 13q fol lowed by deletions of 11q, trisomy 12, and deletions of 17p. Except fo r the TP53 gene at 17p13, no candidate gene affected by these aberrati ons has so far been identified. FISH will be instrumental for the iden tification of such genes because the recurrent aberrations, especially deletions, can be systematically delineated to the resolution level o f several kb. Furthermore, based on the sensitive detection of chromos ome abnormalities by FISH, more accurate correlations between chromoso me abnormalities and prognosis can be performed. Deletion of the TP53 gene at 17p13 have already been shown to be one of the most important independent prognostic factors for survival. Other specific aberration s of clinical significance will likely be identified by the systematic application of interphase cytogenetics on a large series of patients.