ROMA illuminates CLL genomic lesions.

In this issue of Blood, Grubor and colleagues investigate genomic changes in a large series of patients with CLL. They report novel genetic lesions, ascertain the frequency of losses and gains of genomic areas with greater accuracy, track down candidate genes, and analyze intraclonal heterogeneity. D espite its phenotypic homogeneity, chronic lymphocytic leukemia (CLL) is clinically heterogeneous. Some patients have an aggressive disease and a poor prognosis , others an indolent course and a virtually normal life expectancy. 1 The possibility of identifying CLL patients at diagnosis who harbor lesions known to be associated with poor prognosis would offer an opportunity for selective and more effective treatment for some while sparing others from toxic effects of therapy. This has led to a quest for biologically defined prognostic factors, the most widely used being scoring of the mutational status of immunoglobulin (IG)VH genes, expression of surface CD38 or cytoplasmic ZAP70, and fluorescent in situ hybridization (FISH) analysis for specific chromosomal lesions. 2 FISH and comparative genomic hybridization (CGH) have clearly documented the clinical importance of the genetic subtyping of CLL. 3 With FISH or CGH as compared to conventional cytogenetics, a much higher frequency of CLL patients have been found to have recurrent abnormalities , especially deletions (eg 13q14.2, 11q22-q23, 17p13) while DNA segment gains (such as trisomy 12) are less frequent. 1 Still, with both FISH and conventional CGH platforms 15% to 20% of samples do not have detectable abnormalities. Here begins the relevance of the findings described by Grubor et al, who use Repre-sentational Oligonucleotide Microarray Analysis (ROMA), 4 a form of CGH that allows the examination of genomic changes in tumor samples at an unprecedented resolution. The power of ROMA technology is in the numbers, as only 1.7% (1/58) samples did not have detectable lesions. The implication is that ROMA brings to light lesions too fine to be identified with cytogenetics/FISH or lower-resolution CGH technologies. For example, a lesion as small as 20 kb could be identified. While an increased resolution is expected to yield a more accurate definition of genetic lesions, it also has an inherent risk—which is irrelevant at lower resolution—that is, to confuse the normal copy number variation of genome that frequently occurs in the human gene pool with leukemia-associated abnormalities. To safeguard against this problem, the authors have obtained DNA from both CLL cells and neu-trophils from each patient, providing an internal normal genome …