Aberrations Detected By FISH in Brazilian Multiple Myeloma Patients
Authors: Chauffaille Maria de Lourdes , Perazzio Aline Dos Santos Borgo 
Published: November 2019

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy with genetic abnormalities that comprise the most important prognostic factors. Chromosomal aberrations also influence the evolution and treatment refractoriness. Abnormalities progress in a stepwise way, from the pre-malignant stage of monoclonal gammopathy of undetermined significance, through smoldering until symptomatic MM. While marrow karyotype reveals only <30% of aberrations, FISH may show in up 90% of cases. FISH has become an essential tool in diagnosis, risk-classification and personalized therapy. There are two main groups of abnormalities: primary (trisomies and 14q or IGH gene translocations) which occur in plasma cells evolving into clonal stage, and secondary (-13/13q-, del(17p), +1q21/del1p), occurring during disease progression. As there are few reports of genetic aberrations in Brazilian MM patients, the objective of this study was to enlarge the casuistic and compare results.
Objective: To dissect FISH aberrations detected in a larger set of Brazilian MM patients.
Material and Methods: From Jan 2012 to Nov 2017, 417 MM patients were selected for the study. FISH was performed on isolated CD138 immunomagnetic beads plasma cells, using probes for 6q23.3 (MYB), 11q12.1 (D11S3347), 11q22.3 (ATM), 13q14.3 (D13S319-D13S25-RB1), 13q34 (D13S1825-LAMP1), 14q32 (IGH, break-a-part), 17p13.1 (TP53) IGH/FGFR3, IGH/CCND1 and IGH/MAF, according to the manufacturer´s instructions. At least 100 interphase cells were counted, and results described according to ISCN 2016. The cut off level was in-house established by mean +2 standard deviation from normal bone marrow controls.
Results: Patients mean and median ages were 63.9 and 64y, respectively. M:F rate was 1.5:1. FISH showed abnormalities in 80% (333) of cases. Considering primary abnormalities: IGH-FGFR3 rearrangements were detected in 22.5% (30 patients), IGH-CCND1 in 57.2% (76), IGH-MAF in 3.7% (5 patiens), and 16.6% (22) IGH-unidentified gene. The most frequent trisomies were: 6 (62 patients), 11 (93 patients) and 17 (33 patients), some co-occurring and others isolated. 89 (31.6%) cases presented >3 aberrations, from which 25% had del(17p) (TP53) as well; 65 cases had three aberrations and 127 less than three abnormalities. Referring to secondary aberrations, 67(20.1%) cases presented del(13q) (RB1 and LAMP) and 32 (9.6%) del(17p) (TP53). Stratifying to prognosis (mSmart 2.0) 37 (10%) patients were considered as high-risk; 92 (27.6%) intermediate; 160 (48%) standard and 44 were not classified.
Discussion: Comparing these results to literature reports, at diagnosis, Brazilian MM patients have mean and medium ages younger than European and North American populations. This type of difference has been detected in other hematopoietic neoplasias as well. FISH results were thoroughly similar referring to the total percentage and type of aberrations, but some variations in the frequency of aberrations were observed. Most patients were classified in the standard-risk group, presenting hyperdiploidy (30%) and t(11;14)(19%). The percentage of high-risk patients was reasonable (10%). Most of those with more than three aberrations also presented del(17p), a marker of adverse cytogenetics, as expected. The frequency of del(17p) was not unexpected, most being heterozigous deletion. Cases described as IGH-unidentified gene rearrangements may have been due to the unavailability of probes for chromosomes 6 and 20, at the time of the study. The same happened to 1q gain and del(1p). In summary, the spectrum of aberrations detected allowed identifying high-risk patients, choosing adapted therapy and improving outcomes.

Disclosures
No relevant conflicts of interest to declare.