Trisomy 4, a New Chromosomal Abnormality in Waldenstrom’s Macroglobulinemia.
Authors: Terre C. , Guyen-Khac F. N. , Barin C. , Moziconacci M.J. , Eclache V. , Leonard C. , Farhat H. , Bouyon A. , Rousselot P. , Choquet S. , Leblond V. , Castaigne S. 
Published: April 2020

Background:

Waldenstrom’s Macroglobulinemia(WM) is a rare B-cell disorder characterized by the accumulation of monoclonal lymphoplasmocytic cells and a serum monoclonal IgM protein. The genetic basis of this disorder is poorly understood. Molecular cytogenetic abnormalities differ from those reported for multiple myeloma, lymphomas, and B-cell chronic lymphocytic leukemia. One recurrent abnormality, deletion of the long arm of chromosome 6, was reported with a high prevalence (23–50%), but seems associated with advanced disease and clonal evolutions.

Aims :

As data on molecular changes in WM are limited, we used interphase fluorescence in situ hydidization (IP-FISH) to evaluate the prevalence of trisomy 4 in WM patients.

Material and methods:

39 patients with a diagnosis of WM , according to the Workshop classification, were included: 28 men and 11 women. Mean age at diagnosis was 66 years (48–84 years).

Mean percentage of bone marrow lymphoplasmocytic cells was 47% (13–97%).

Conventional cytogenetic was performed after 72 or 96 hours culture with TPA, at diagnosis for 23 patients and 3.8 years median (6 months–9 years) after for 13.

FISH study was carried on cytogenetic cryopreserved pellets using a CEP-4 probe (Qbiogene, Illkirsch, France)

Results:

Karyotypes were available for 37cases (2 failures): 24 were normal, 3 had a trisomy 4, (2 as the sole abnormality), 2 a partial loss of 17p (one deletion and one additional material), 2 a loss of sexual chromosome, 1 a t(11;18), 1 a partial duplication of 17q, 1 a partial monosomy 5q with insertion of unknown material in 4q, 1 a complex karyotype with a partial trisomy 4 and 2 with abnormal independent clones.

IP-FISH: The 3 complete trisomies 4, already seen by conventional cytogenetic, were confirmed and 4 others were detected. The mean percentage of cells with trisomy 4 was 31% (11–52%) (cut-off 2%, median+4SD)

Discussion:

We found that 7 of 39 patients (18%) with WM harboured a complete trisomy 4 with IP-FISH, contrary to only three (8%) with conventional cytogenetic. This study, performed in interphase, is independent of the proliferation rate. Therefore the prevalence is probably underestimated since IP-FISH was realized in unselected cells: in 11 patients the percentage of clonal involvement of the bone marrow was under 30% and it was unknown in 6 patients. The mean percentage of bone marrow lymphoplasmocytic cells was higher for patients with trisomy 4 (63%) than in others (43%). The trisomy 4 was the only abnormality in 2 of the 3 karyotypes where it was identified and in one sporadic case reported previously. Thus it could be a specific primary genetic event in the WM. Moreover, the detection of one partial trisomy 4 define an interesting region with potential oncogene. cKIT, located at 4q12, was a good candidat gene and molecular studies are in process.

Conclusion:

We identified a new recurrent chromosomal abnormality in WM, the trisomy 4, with a prevalence of at least 18%. The exact prevalence of this abnormality should be determined by IP-FISH study in CD19+ and CD138+ selected cells. This abnormality could be primary and could lead to elusive the molecular pathogenesis of WM.