Biology and Clinical Importance of Recurrent Genomic Deletions in Chronic Lymphocytic Leukemia.

Abstract SCI-30 The genome of ∼80% of patients with CLL harbors one or more recurrent sub chromosomal deletions. The most frequent of these are interstitial deletions on the long arm of chromosome 13 (del13q14, ∼50% incidence), chromosome 11 (del11q22.3, ∼10% incidence) and the short arm of chromosome 17 (del17p, ∼7-10% incidence). Additional recurrent losses, including at 6q and 14q, have been described. Given the important observations that the presence of del17p or del11q predicts for relatively short overall survival in cohorts of CLL patients, efforts have been directed at identification of genes that are involved in the biology of these lesions. The adverse clinical prognosis of del17p in CLL appears to be due to associated p53 mutations in the majority of afflicted cases as well as absent p53 expression in a minority of cases. Nonetheless, comparative analysis of deletions on 17p across hematological malignancies clearly demonstrated that del17p in CLL invariably removes most of the short arm of chromosome 17 (∼18-21 Mb in length), while 17p deletions in lymphomas or acute myelogenous leukemias are very heterogeneous and often substantially shorter. Thus additional genes other then p53 are likely contributing to the biology of del17p within the CLL cell and efforts are underway to identify such genes. Deletion 11q22.3 in CLL usually is large spanning many megabases of DNA and all classical 11q22.3 deletions (defined through FISH testing) result in the loss of one ATM allele. Given that a subset of these cases (∼30-50%) also harbors mutated or non-functional ATM on the retained allele, a subset of CLL with del11q22.3 (∼3-5 % of all CLL) is completely deficient in ATM function. It is this subset of cases that is clinically more aggressive than CLL with del11q and wild type ATM . Further, precise mapping of del11q in CLL using high resolution SNP-array technology has identified previously unrecognized additional minimal deleted regions that do not span ATM as well as frequent deletions of additional genes critical to the cellular response to DNA-double strand breaks. Thus the biology of del11q in CLL is mediated by additional genes other than ATM . Given that ATM mutations appear late in CLL disease progression, it is likely that these unidentified genes confer selective advantages on CLL cells with del11q and efforts are underway at identifying such del11q-associated deregulated or mutated genes. Deletion 13q14 is the most frequent genomic aberration in CLL and genomic deletions mapping to that region are also very common in mantle cell lymphoma and multiple myeloma. Unlike del17p or del11q, del13q14 in CLL can involve both chromosomes and in addition displays significant length heterogeneity. These findings have motivated proposals for del13q14 subtypes based on inclusion (type II) or exclusion (type I) of Rb in the deleted chromosomal segments. While isolated del13q14 is not an adverse prognostic marker, heterogeneity in outcome based on affected del13q14-associated genes will likely emerge in the future. Finally, a subset of previously untreated CLL (∼15-30%) displays elevated genomic complexity as measured through multiple independent techniques and it is this subgroup of patients that has aggressive CLL. Additional efforts are needed to better understand the molecular parameters contributing to genomic complexity in CLL as well as making routine genomic complexity assessments available to the treating physician. Disclosures Malek: Cephalon: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Affymetrix: Research Funding.