13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

Abstract

Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio ¼ 12.3; P ¼ 0.005), (b) in progressive patients, class II deletions were enriched (P ¼ 0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (Po0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines

“…DLEU2 is the host gene of miR-15a/16-1, and its essential role in providing the primary transcript of these microRNAs is demonstrated by the complete ablation of miR-15a/ 16-1 production on specific deletion of the DLEU2/dleu2 promoter region 44 (and our own unpublished observations); this particular deletion that leaves the miR-15a/16-1 gene cluster intact has been described to occur in vivo in several CLL cases. 17,40,44 An unresolved issue is whether DLEU2 has any additional roles, because experiments aimed at identifying an independent function for the DLEU2 transcript, the sequence of which does not display homology to any other long noncoding RNA, have not yielded any insights. 22,44 A further question regarding a potential function of DLEU2 transcripts is whether the processed pseudogene DLEU2L, encoded on chromosomal region 1p22, may compensate for the loss of DLEU2 in CLL with 13q14 deletions.…”

“…Subtypes of 13q14 deletions have been identified with loss of DNA centromeric to the DLEU2/mir-15a/16-1 cluster, a fraction of which includes the retinoblastoma (Rb1) tumor-suppressor gene, 16 and that have a less favorable prognosis. [40][41][42][43] Inactivation of miR-15a/16-1, the expression of which is invariably ablated in all CLL with 13q14 aberrations, has functionally overlapping effects with Rb1 deletion, because miR-15a/16-1 down-regulates the expression levels of G 0 -G 1 /S-phase-promoting proteins that normally lead to Rb phosphorylation and result in cell-cycle entry. A concomitant deletion of both miR-15a/16-1 and Rb1 may accelerate the disease course.…”

PHF11 promotes DSB resection, ATR signaling, and HR

“…Here we used dysfunctional telomeres to identify PHF11 (plant homeodomain finger 11) as a DDR factor. PHF11 is frequently methylated in Ewing's sarcoma (Alholle et al 2013), codeleted with a cluster of genes in CLL (Parker et al 2011), and deleted in 10%-20% of prostate cancers (cBioPortal for Cancer Genomics, http://www.cbioportal .org). PHF11 is most abundant in lymphocytes and is thought to act as a transcription factor that promotes class switching in the IgE locus in B cells (Clarke et al 2008;Ikari et al 2014).…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…Moreover, recent evidence has revealed heterogeneity within the 13q14 deletions, subdividing them into two distinct subtypes (type I deletions, < 2 Mb in size, not including the RB1 gene, and type II deletions, > 2 Mb in size, including RB1). The 13q14 type I and II deletions in CLL are biological and prognostic distinct entities Parker et al, 2010]. Routine diagnostic analysis often comprises FISH analysis, utilizing locus-specific probes covering only the gene DLEU1/2, which permits the detection of deletions at the 13q14 locus, but not the accurate breakpoints or size of the deletion.…”