14q deletions are associated with trisomy 12, NOTCH1 mutations and unmutated IGHV genes in chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract

Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.

Mutational and cytogenetic analyses of 188 CLL patients with trisomy 12: A retrospective study from the French Innovative Leukemia Organization (FILO) working group

“…13,14 Other common CAs identified by means of conventional and molecular cytogenetic approaches include del (13)(q14), del (11)(q22-23), del (17) (p13), gain (2)(p), and del (6)(q21). 18 Indeed, accompanying chromosomal aberrations such as additional trisomies (tri18 and/or tri19), [18][19][20] 14q32 translocations (t [14;18](q32;q21) and t (14,19)(q32; q13)), [21][22][23][24][25] and 14q deletions 26,27 are commonly observed in tri12 CLL, and it has been suggested that patients harboring additional trisomies have better outcomes than patients with isolated tri12. [14][15][16][17] Tri12 was usually considered to be an intermediate-risk genetic lesion in newly diagnosed CLL and in the context of chemotherapy treatment, 14 although recent reports suggest that it confers more complex and heterogeneous clinical behavior.…”

“…[14][15][16][17] Tri12 was usually considered to be an intermediate-risk genetic lesion in newly diagnosed CLL and in the context of chemotherapy treatment, 14 although recent reports suggest that it confers more complex and heterogeneous clinical behavior. 27,30,31 Recent NGS analyses show that the CLL genome displays a high degree of heterogeneity, both across patients and in a given patient. 18 Compared to CLL lacking this cytogenetic abnormality, tri12 CLL has a more atypical morphology and immunophenotype, 28,29 more frequent expression of the poor prognostic markers CD49d and CD38, more frequent NOTCH1 mutations, and unmutated (UM) IGHV gene status.…”

“…[14][15][16][17] Tri12 was usually considered to be an intermediate-risk genetic lesion in newly diagnosed CLL and in the context of chemotherapy treatment, 14 although recent reports suggest that it confers more complex and heterogeneous clinical behavior. 18 Indeed, accompanying chromosomal aberrations such as additional trisomies (tri18 and/or tri19), [18][19][20] 14q32 translocations (t [14;18](q32;q21) and t (14,19)(q32; q13)), [21][22][23][24][25] and 14q deletions 26,27 are commonly observed in tri12 CLL, and it has been suggested that patients harboring additional trisomies have better outcomes than patients with isolated tri12. 18 Compared to CLL lacking this cytogenetic abnormality, tri12 CLL has a more atypical morphology and immunophenotype, 28,29 more frequent expression of the poor prognostic markers CD49d and CD38, more frequent NOTCH1 mutations, and unmutated (UM) IGHV gene status.…”

“…18 Compared to CLL lacking this cytogenetic abnormality, tri12 CLL has a more atypical morphology and immunophenotype, 28,29 more frequent expression of the poor prognostic markers CD49d and CD38, more frequent NOTCH1 mutations, and unmutated (UM) IGHV gene status. 27,30,31 Recent NGS analyses show that the CLL genome displays a high degree of heterogeneity, both across patients and in a given patient. [8][9][10] Among somatic genetic alterations, copy-number abnormalities may be the earliest events in CLL, with two distinct points of departure involving del(13q) and tri12.…”

Second Cancers and Richter Transformation Are the Leading Causes of Death in Patients With Trisomy 12 Chronic Lymphocytic Leukemia

“…22 It has been shown recently that del(14q), often associated with +12 as well as with unmutated IGHV and NOTCH1 mutations, portends a poor prognosis. 38 The number of patients with del(14q) in our study is small. However, our findings suggest that evaluation for this abnormality, either by conventional cytogenetic analysis and/or FISH analysis, may have prognostic relevance in these patients.…”