The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and affects predominantly older adults. The clinical course and biology of this disease are heterogeneous; some patients die within months of diagnosis, whereas others live longer than 20 years.1 The Rai and Binet staging systems help identify patients who have more advanced disease and require treatment.2 Because most patients present with early- or intermediate-stage disease, additional markers are needed to stratify patients who are at increased risk of disease progression with concomitant decreased survival. Chromosome abnormalities provide prognostic information in CLL.3 The prognostic impact of cytogenetics on survival is underscored by a median survival of 15 years in those patients with diploid cytogenetics compared with only 6 years in those who have complex abnormalities.4 Conventional cytogenetic analysis detects chromosome abnormalities in up to 50% of patients with CLL. The most frequent chromosomal changes are deletion of 13q, 11q, 17p, 6q, and trisomy 12.5 However, given the low mitotic activity of the CLL clone (most are in the G0 phase), conventional cytogenetic techniques may not detect the full complement of chromosome changes. Fluorescence in situ hybridization (FISH) can identify chromosome abnormalities in up to 80% of patients with CLL by detecting aberrations in both dividing cells and interphase nuclei.6 FISH may reveal clonal changes in some patients found to have normal karyotypes. Although cytogenetic analysis can detect the 13q deletion in 20% of cases, FISH increases the detection of 13q deletion in more than 50% of cases.7 Deletions of 11q and 17p are poor prognostic features for patients with CLL and lead to a shortened survival. Conversely, the presence of 13q deletion confers a good prognosis.7 The genetic significance of 13q deletion is not fully known. The chromosome band 13q14 carries the retinoblastoma gene (RB1), and it was originally thought that abrogation of this tumor suppressor gene was implicated in the pathogenesis of CLL. However, biallelic deletion of RB1 is rare, suggesting that there were other genes involved. One study of 75 patients with CLL showed that 33 (44%) carried either monoallelic or biallelic deletion of 13q. The deletion frequency was 16 of 75 (21%) at the RB1 gene, 33 of 75 (44%) at the D13S319 locus, and 29 of 75 (39%) at the D13S25 locus. In 16 of 75 (21%) patients, a large deletion covering all 3 of these loci was found.8 Other mechanisms may be responsible for clonality,9 including reciprocal translocations involving band 13q14 that are associated with D13S25. Another area thought to be implicated in the disease process is D13S272. However, subsequent mutation analysis of 2 candidate genes, Leu1 (deleted in lymphocytic leukemia 1) and Leu2, did not show inactivation of these genes. More recent studies show that microRNA genes miR-15a and miR-16-1 map to 13q14.3. Allelic loss in this area correlated with deletion of genes in CLL, suggesting that these 2 microRNAs can function as tumor suppressor genes.10 It has been hypothesized that homozygous deletion of the 13q locus might lead to a more accelerated disease trajectory. In this study, an analysis was performed in patients with CLL and either monoallelic or biallelic 13q deletion to detect any prognostic differences.