14q Deletions Are Recurrent Aberrations in CLL and Other Mature B-Cell Neoplasms and Show a High Coincidence with An Unmutated IgVH Status and Trisomy 12, and Are Associated with An Intermediate Overall Survival and a Shorter Time to Treatment.

Abstract 1262

Poster Board I-284

14q deletions are rare aberrations in malignant neoplasia but recurrent in hematologic malignancies, where they occur most frequently in CLL and other mature B-cell neoplasms. The breakpoints and the size of the 14q deletion have not been exactly characterized in a larger cohort yet. Based on chromosome banding analysis we identified 47 cases with 14q deletion out of 3054 cases (1.5%) with mature B-cell neoplasms (CLL: 1863, CLL/PL: 92, other: 1099). 32 cases with 14q deletion were classified as CLL, 5 as CLL/PL and 10 as other mature B-cell neoplasms based on immunophenotyping or cytomorphology. Therefore, the incidence of 14q deletions was 1.7% in CLL, 4.7% in CLL/PL and 0.9% in other mature B-cell neoplasms. These cases were further analyzed by a panel of FISH probes localized in 14q22.1 (BAC RP11-218E20), 14q24.1 (BACs PR11-35D12, RP11-226F19), 14q32.33 (BAC RP11-521B24) (BlueGnome, Oxford, UK) and the IgH-locus (14q32.3). The study revealed that 14q deletions are heterogeneous in size. A breakpoint cluster on the centromeric side was identified in 14q24.1 between BAC PR11-35D12 and BAC RP11-226F19 (62% of cases), whereas the most frequent breakpoint on the telomeric side was within the IgH-locus (14q32.3) between the IgH3'-flanking probe and IgHV probe (45% of cases). In 16 cases (34%) breakpoints occurred within 14q24.1 and within 14q32.3. In 19% of patients the 14q deletion was the sole abnormality whereas 30% showed one, 15% two and 36% three or more additional aberrations. Trisomy 12 (45%) was the most frequent aberration accompanying 14q deletion. In comparison to a cohort of 1579 cases with mature B-cell neoplasms without 14q deletion which were analyzed for IgVH mutation status in the same time period, patients with 14q deletions showed more often an unmutated IgVH status (39% vs. 61%, p=0.001). In the subgroup with breakpoint in 14q24.1 and 14q32.3 even 82% showed an unmutated IgVH-status. This subgroup was also associated with a CLL immunophenotype (81%). Clinical follow up data was available in 28 patients. CLL and CLL/PL with 14q deletion were compared to 390 CLL and CLL/PL cases without 14q deletion. While overall survival (OS) did not differ between both groups (OS at 3 yrs 86.4% vs. 88.7%, p=0.195), time to treatment (TTT) was significantly shorter in cases with 14q deletion (21.0 months vs. 80.1 months, p=0.015). Next, all 418 cases were assigned into 6 subgroups with known prognostic relevance: 1) 14q deletion, 2) 17p deletion, 3) 11q deletion, 4) trisomy 12, 5) 13q deletion as the sole abnormality, and 6) none of the mentioned abnormalities. OS at 3 yrs was 86.4%, 31.4%, 77.5%, 96.9%, 93.4% and 93.9%, respectively. For TTT the respective data were 21.0 months, 21.6 months, 20.9 months, not reached, 79.6 months and 147.0 months. In conclusion, 14q deletions are recurrent abnormalities in CLL and other mature B-cell neoplasms. Comparable to 13q deletions the size of 14q deletions varies. However, recurrent breakpoints in 14q24.1 and 14q32.3 were identified. Our data suggest to add FISH probes for 14q24.1 and for the IGH locus to the standard FISH panel in CLL and other mature B-cell neoplasms to pick up cases with 14q deletion, who would otherwise be assigned to “normal” FISH subgroup. In conclusion, 14q deletions are frequently accompanied by trisomy 12, an unmutated IgVH status and are associated with an intermediate overall survival and a shorter time to treatment comparable to other high risk cytogenetic aberrations (17p deletion, 11q deletion).