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The relevant clinical data of 21 cases with the del(14)(q24.1q32.33) (index cases) are summarized in Table 1. There were 14 male and 7 female patients (2.0 M/F ratio) ranging in age from 52 to 90 years (mean 71.6). These cases represented a spectrum of B-cell malignancies including typical CLL (n=8), atypical CLL showing either morphological or immunophenotypic discordances (for example, expressing CD22 (n=4) and/or FMC7 (n=2), and/or lacking expression of CD23 (n=2) or CD5 (n=1)) (n=7), low-grade B-NHL (marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), not otherwise specified NHL (NOS-NHL)) (n=3) and MM (n=3). Case 17, diagnosed as MZL, transformed to a fatal DLBCL 2 years after diagnosis. Among CLL patients, five presented in Binet stage A, two in stage B and five in stage C (no available staging data in two cases). The majority of patients (18/21) required therapy and when given (alkylators), they responded initially (data not shown). Nine patients are alive after 4–88 months (median 35) from diagnosis. Twelve patients died (0.75–118 months, median 21 months) after diagnosis, either from progressive disease (n=5), infection (n=4), both disease and infection (n=1) or from unrelated reasons (other neoplastic disease, n=2). (Cyto)genetic features of index cases are summarized in Table 1. All but two cases (88%) showed a simple karyotype with 1–3 chromosomal changes per case (an average of 1.2). In five cases (30%), the del(14) was the sole abnormality. The most frequent chromosomal change associated with the del(14) was trisomy 12, evident in eight cases (47%) including five in which it appeared as the only additional change. IGVH mutation analysis performed in 15 index cases (Table 1) showed lack of somatic mutations (98–100% homology to germline VH genes) in 10 cases, somatic hypermutations (94.7–91.5% homology to germline VH genes) in 3 cases and presence of unmutated (100% each) as well as mutated (96.7 and 95.2%, respectively) VH sequences in 2 cases (nos. 18 and 19). In both these cases and in case 3 (unmutated CLL (umCLL)), usage of two different VH segments was identified. Altogether, 15 different VH segments were used, including 3–30 detected in 3 cases (including cases 3 and 18 with biclonal rearrangements) and 2–70 detected in 2 cases (cases 18 and 19, both with biclonal rearrangements).
Table 1 Clinical, molecular and cytogenetic findings in 21 cases with the identified del(14)(q24.1q32.33)
For a more precise mapping of the del(14)(q24.1q32.33) breakpoints, we used FISH with a pair of fosmid clones flanking ZFP36L1 (WI2-1846M8; WI2-1710N10) and two IGCH cosmid clones, cos3/64 covering JH, Cμ and Cδ3 and cosα1 harboring Sα1/Cα1 sequences4 (Figure 1c). Moreover, we applied genomic qPCR with a set of primers selected for the following sequences: A and D, flanking ZFP36L1; B and C, coding ZFP36L1; E, representing IGHA2; and F and G flanking the 5′enhancer (Eμ) of IGCH (Table 2) (Supplementary Table 1). Results of this compiled FISH and qPCR analysis are shown in Table 2. Briefly, the 14q24.1 breakpoints were mapped to the region proximal to ZFP36L1 (Ax2, B/Cx1) in three cases, within the gene (A/B-x2, C/D-x1) in six cases and distal to ZFP36L1 (A/B/Cx2, Dx1) in three cases. The 14q32.33 breakpoints were shown to be centromeric to sequences flanking Eμ (Fx2/Gx2) in 10 cases, occurred within the region coding Eμ (Fx1/Gx2) in 3 cases and were telomeric to all three analyzed IGCH sequences (Ex1/Fx1/Gx1) in 1 case (no. 3). The involvement of IGH in this particular del(14)(q24.1q32.33) (as well as six other deletions identified by aCGH; Figure 1a) suggested that this aberration may operate in a translocation-like manner and activate an unknown oncogene at 14q owing to juxtaposition to the Eμ enhancer of IGH. To identify the affected gene, we analyzed the expression pattern of ZFP36L1 and 14 other genes mapped within the proximal 3 Mb (RAD51L1, ZFYVE16, RDH11, RDH12, ARG2, PLEKHH1, PLEK2, EIF2S1, ATP6V1D, MPP5, CN054, GPHN, NP_001004331) by qPCR analysis in 12 available cases (marked in Table 1) (Supplementary Table 1). MAX located 3.8 Mb from the breakpoint was included as an additional candidate gene. Four CLL and two myeloma cases without del(14) were used as controls. The results did not show any uniformly overexpressed gene and displayed a very inconsistent expression pattern of all evaluated genes in the index cases (Supplementary Table 2). The most frequently upregulated gene was RAD51L1 showing 2- to 18-fold increased expression when compared with controls in eight cases. Assuming that the gene targeted by del(14) (q24.1q32.33) escaped qPCR analysis, a global expression analysis using Human Genome U133 Plus 2.0 Affymetrix microarrays was performed on lymph nodes material from two cases (nos. 7 and 8; both umCLL). RNA extracted from involved lymph nodes from two umCLL cases without del(14) and two reactive lymph nodes was included as control. This global expression analysis identified 24 genes that were at least twofold upregulated, and 25 downregulated genes when compared to control CLLs (Supplementary Table 3 and Supplementary Figure 1). The former group included only one gene located on chromosome 14, CHURC1. This gene, mapped at 14q23.3 (64.45 Mb), was found to be 3.36-fold upregulated in the two analyzed cases. qPCR analysis, however, showed inconsistent expression pattern of CHURC1mRNA (and control RGPD4 and PLCD1 genes found to be upregulated in cases 7 and 8) in the remaining 10 analyzed cases (Supplementary Table 2).
Table 2 Results of the fine mapping of the 14q24.1 and 14.q32.33 breakpoints in 21 index cases by FISH and qPCR
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This work was supported by the KULeuven Research Foundation (BIL03/12 and BIL05/59) and Grant G.0610.07 from the Fund for Scientific Research (FWO), Flanders, Belgium.
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Authors and Affiliations
Department of Human Genetics, Catholic University Leuven, Leuven, Belgium
H Pospisilova, M Baens, L Michaux, M Stul, P Van Loo, J Vermeesch, A Hagemeijer, P Vandenberghe, J Cools, P Marynen & I Wlodarska
Microarray Facility VIB, Catholic University Leuven, Leuven, Belgium
P Van Hummelen
Department of Hemato-Oncology, Palacky University Olomouc, Olomouc, Czech Republic
H Pospisilova & M Jarosova
Center of Oncocytogenetics, General Faculty Hospital, Prague, Czech Republic
Z Zemanova & K Michalova
Department of Pathology, St Jan Hospital, Brugge, Belgium
I Van den Berghe
Department of Haematology, Belfast City Hospital, Belfast, UK
H D Alexander
Department of Pathology, Catholic University Leuven, Leuven, Belgium
C De Wolf-Peeters
Flanders Interuniversity Institute for Biotechnology (VIB), Catholic University Leuven, Leuven, Belgium
M Baens, P Van Loo, J Cools & P Marynen
Department of Electrical Engineering, Bioinformatics Group, Catholic University Leuven, Leuven, Belgium
Pospisilova, H., Baens, M., Michaux, L. et al. Interstitial del(14)(q) involving IGH: a novel recurrent aberration in B-NHL.
Leukemia21, 2079–2083 (2007). https://doi.org/10.1038/sj.leu.2404739
