Clustering of Prognostically Important Cytogenetic Aberrations in Multiple Myeloma with Translocation t(11;14)) (q13;q32)
Authors: Trakhtenbrot Luba , Stanevsky Anfisa , Novikov Ilya , Leiba Merav , Nagler Arnon , Amariglio Ninette 
Published: October 2019

Abstract
Abstract 3961
The prognostic value of the translocation t(11;14)(q13;q32) in patients (pts) with Multiple Myeloma (MM) is not fully resolved. Using FISH, t(11;14) can be identified in 15–20% of patients with MM and in 15–30% of cases with MGUS. The clustering of prognostically established cytogenetic aberrations (CAs), namely gains of 1q and deletions of 13q,17p, 1p, 16q, as well as deletions of IGH segments, was analyzed by combined morphology and FISH techniques in 94 MM and 8 MGUS pts carrying the t(11;14)(q13;q32) translocation. We used commercially available LSI CCND1, LSI IGH/CCND1, LSI IGH, LSI IGH/MAF and LSI 13 (RB1) probes (Vysis, Downers, Grove, IL)and p53 deletion and CKS1B/CDKN2C amplification/deletion probes (Cytocell Ltd., Cambridge, UK). CAs were not found in MGUS patients and in 37/94 MM patients (39.4%). In 57 MM patients one to five CAs were found: one in 14, two in 21, three in 13, four in 5 and five in 4 patients.
The association between different CAs within the group with t(11;14) translocation were studied using the kappa statistics, Odds Ratio and Fisher exact tests. We did cluster analysis of the binary variables (presence/absence) of each of CAs using median linkage with Yule measure of similarity. The Yule measure Y for two aberrations is defined as (ad-bc)/(ad+bc), where “a” is the number of patients with both aberrations, “d” is the number of patients with no one of the two aberrations, and “b” and “c” are the numbers of persons with only one of the aberrations. All calculations were done with STATA 12 SE software.
A strong association was found between four CAs: del(13q), del (IGH), del(17p) and del(16q).
A high correlation was also found between 1q gain and 1p loss, while correlation of these CAs with the other four CAs was not detected (Tab.1). Cluster analysis led to the identification of a cluster including del(13q), del (IGH), del(17p) and del(16q), while 1p loss and 1q gain were identified as a separate cluster. The apparently close connection between CAs from the same cluster raises the question whether these aberrations occur concurrently as the result of a single oncogenic event. It is possible to suggest that in the oncogenesis of MM with t(11;14) the formation of these clusters is not related and results from different oncogenic events.
In conclusion we were able to demonstrate the strong association between del(13q), del (IGH), del(17p) in MM with translocation t(11;14) using a combination of morphology and FISH analyses, that was overlooked in previous investigations. The study of association between CAs additional to t(11;14) in MM patients is important for evaluating the prognostic significance of the combination of CAs and can provide insights into the biology of MM.
Table 1. Chi-square exact tests and odds ratio (OR) test for the analysis of coexistence of different CAs Number in pairs* Fisher' P-value CA #1 CA#2 −/− +/− −/+ +/+ Kappa/p-value OR(95%CI) del(13q) del (IGH) 58 7 2 35 0.8145 (<0.0001) 145 (28.5–737.5) <0.001 del(13q) del(17p) 59 35 1 7 0.1797/0.0028 11.8 (1.39–99.95) 0.008 del(13q) loss 1p 55 40 5 2 −0.0408/0.7587 0.55 (0.102–2.98) 0.697 del(13q) gain 1q 51 29 9 13 0.1718/0.0269 2.54 (0.87–7.56) 0.085 del(13q) del(16q) 55 26 5 16 0.3218/0.0879 6.77 (2.04–25.7) <0.001 del (IGH) del(17p) 63 31 2 6 0.1581/0.0088 6.1 (1.16–31.97) 0.025 del (IGH) loss 1p 62 33 3 4 0.0751/0.1170 2.5 (0.53–11.87) 0.252 del (IGH) gain 1q 55 25 10 12 0.1868/0.0221 2.64 (0.9–7.75) 0.078 del (IGH) del(16q) 60 21 5 16 0.392/<0.0001 9.14 (2.7–35.1) <0.001 del(17p) loss 1p 87 8 7 0 −0.079/0.7881 – 1.0 del(17p) gain 1q 76 4 18 4 0.1713/0.0208 4.22 (0.7–24.57) 0.064 del(17p) del(16q) 76 5 18 3 0.1053/0.1083 2.53 (0.36–14.31) 0.356 loss 1p gain 1q 78 2 17 5 0.2687/0.0004 11.47 (1.65–125.5) 0.005 loss 1p del(16q) 76 5 19 2 0.0445/0.2942 1.6 (0.14–10.68) 0.631 gain 1q del(16q) 67 13 14 8 0.2045/0.0194 2.95 (0.87–9.40) 0.070 * Absence(−)/Presence(+) of CA#1/CA#2.

Disclosures:
Nagler: medac, germany: Research Funding.