ANALYSIS OF CHROMOSOMAL ABNORMALITIES ASSOCIATED WITH HIGHER RISK OF MALIGNANT TRANSFORMATION OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

Sborník

Background. Monoclonal gammopathy of undetermined significance (MGUS) is a precancerosis permanently associated with higher risk of transformation into malignant disease. Similarly to multiple myeloma patients, specific chromosomal aberrations in bone marrow plasma cells (PCs) in MGUS persons were reported, especially del(13)(q14), del(17)(p13), IGH rearrangement, 1q21 gain and hyperdiploidy (Lopez-Corral, L. et al., Clin. Cancer Res. 2011). Some of them are considered to be prognostic factors determining potential risk of MGUS transformation to malignant condition. Aims. 1) Examination of specific chromosomal abnormalities in the MGUS persons by I-FISH. 2) Assessment of impact of phenotypically abnormal PCs (aPCs; CD138+CD19-CD56+/-) separation on the frequency of monitored chromosomal abnormalities. 3) Evaluation of potential prognostic value of the observed chromosomal abnormalities. Methods. We analyzed 60 MGUS persons: 36M/24F; age median 64 years; follow- up median 26 months. By interphase fluorescence in situ hybridization (IFISH) we examined following chromosomal abnormalities: del(13)(q14), del(17)(p13), IGH rearrangement, t(11;14), t(4;14), t(14;16), 1q21 gain and hyperdiploidy (+5, +9 and +15). The I-FISH was performed on PCs i. identified by fluorescence imunophenotyping (cIg-FISH technique) in 3% (2/60) cases; ii. separated by magnetic activated cell sorting (MACS) or fluorescence activated cell sorting (FACS) using CD138+ marker in 63% (38/60) cases; and iii. separated by FACS using CD138+19-56+/- markers in 33% (20/60) cases. Results. In the cohort of 60 MGUS persons, we found del(13)(q14) in 21% (11/52) cases, del(17)(p13) in 2% (1/52) cases, IGH rearrangement in 71% (31/44) cases, t(11;14) in 50% (2/4) cases, t(4;14) in 10% (4/39) cases, t(14;16) in 6% (1/16) cases, 1q21 gain in 13% (6/48) cases and hyperdiploidy in 15% (7/47) cases. We observed that del(13)(q14) occurred significantly more frequently in persons with hyperdiploidy than with non-hyperdiploidy (67% vs. 17%, p<0,05), and in persons with 1q21 gain than without 1q21 gain (67% vs. 16%.; p<0,05). Comparison of MGUS subgroups with different PCs phenotype enabled to us to show that I-FISH analysis in aPCs allowed to significantly higher frequency of t(4;14) than I-FISH analysis in PCs with CD138+ phenotype (25% vs. 0%; p<0,01). Using stratification model for predicting the risk of MGUS transformation incorporating 3 risk factors (serum monoclonal immunoglobulin ≥15g/l, non-IgG subtype and abnormal FLC ratio) (Rajkumar, S. et al., Blood 2005). MGUS persons were divided into three risk groups: low risk was in 27% (9/33) cases, low-intermediate risk was in 39% (13/33) cases and high-intermediate risk was in 33% (11/33) cases. High risk was not detected in any case. Analysis of frequency of monitored chromosomal abnormalities demonstrated that del(13)(q14) and two or more structural chromosomal abnormalities occurred significantly higher in low-intermediate risk group (45% and 46%) and high-intermediate risk group (33% and 18%) than in low risk group (both 0%; p<0,05). Summary. In this study, we confirm that all monitored chromosomal abnormalities, which usually occur in multiple myeloma, are present in MGUS. We also demonstrated that del(13)(q14) or presence of two or more structural chromosome abnormalities may indicate the higher risk of MGUS transformation to malignant condition.

Support. The study was supported by grants MSM0021622434, GAP304/10/1395, NT11154, NT12425, NT12130.

Haematologica, 2012; 97(s1):  591