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N.A. Heerema et al.
Table 5. Associations between translocations or karyotype complexity with abnormalities detected by interphase fluorescence in situ hybridization.
Complex≥3 Notcomplex P-value
Total
85 244
53 276
MYC
normal x3
Del(17p) No Yes
62 23 237 7 <0.001
34 19 265 11
<0.001
Del(11q) No Yes
64 21 221 23
0.001
38 15 247 29
0.001
Trisomy 12 No Yes
62 23 189 55
0.459
34 19 217 59
0.033
Del(13q) No Yes
51 34 104 140 0.008
32 21 123 153 0.037
Trisomy BCL6 No Yes
75 10 237 7 0.003
43 10 269 7 <0.001
Del(6q)
No Yes FISH
79 6 10 237 7 47
0.207
48 5 1 268 8 56
0.057
Normal
Translocation No translocation P-value
75 239
45 269
0.001
0.001
10 5
8 7
importance of metaphase cytogenetics in order to risk- stratify patients accurately.
The reason a translocation may negate the good progno- sis associated with mutated IGHV is not known. Both the presence of a translocation and a complex karyotype may reflect an underlying genetic instability in CLL. The strong correlation of translocations and complex karyotypes with del(17p), and therefore loss of TP53, which is known to be associated with genetic instability,42 supports this. However, the majority of patients with translocations or complex karyotypes did not have del(17p); thus, other fac- tors must contribute to genetic instability in CLL. Other factors that have been associated with genetic instability include telomere shortening, abnormal ATM, lack of cor- rect kinetochore-microtubule attachment, activation- induced cytidine deaminase, defective mitosis and replica- tion stress. Further investigations are needed to identify whether these or other factors contribute to genetic insta- bility in CLL.
These studies have some significant limitations. These include the relatively low number of patients with translo- cations (85/329), the retrospective nature of the study, and the younger age of patients (median, 60 years). Because of the retrospective nature of this study, some factors, signif- icantly TP53 mutational status and CD49d expression, could not be included as they were not determined rou- tinely. Additionally, both WBC count and b2-microglobu- lin level had a 90-day window, as they were not collected routinely at diagnosis. Also, although all cytogenetic stud- ies were performed within 1 year of diagnosis, they were done at different time-points within this 1-year time- frame.
These results support performing metaphase cytogenet-
oligodeoxynucleotide prospectively at diagnosis on all patients with CLL to verify these findings and to deter- mine whether these findings apply with current targeted therapies. The use of CpG oligodeoxynucleotide stimula- tion is required to adequately define abnormal clones in CLL,5,17,21-26 thus enabling the detection of translocations that are prognostic early in the course of the disease. This additional prognostic factor may help to provide a more precise prognosis for CLL patients, and may more accu- rately define specific treatment options that will be bene- ficial to these patients. While the presence of a transloca- tion has previously been shown to correlate with a poor prognosis, this study indicates that in patients with unmu- tated IGHV, translocations may not affect prognosis. However, detection of a translocation in patients with mutated IGHV may affect prognosis as early as the time of diagnosis.
Disclosures
No conflicts of interest to disclose.
Contributions
NAH did the research. NAH and NM designed the research and wrote the paper. ASR and QZ performed the statistical analysis. LAA, MRG, KJM, JW, FA, ML, AG, CC and JCB contributed samples and data. All authors contributed to writing and finalizing the manuscript and approved its submission.
Funding
This work was supported by Leukemia and Lymphoma Society SCOR grant #7004-11, NCI-7 P50 CA140158-02, and NCI-P30 CA016058, which supports the OSU Comprehensive Cancer Center’s Shared Resources, and the D Warren Brown Foundation.
ic analysis on cultures stimulated
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