Prognostic Relevance of t(4;14) and Expression of FGFR3 and TACC3 in Newly Diagnosed Patients with Multiple Myeloma.
Authors: Terragna Carolina , Renzulli Matteo , Testoni Nicoletta , Nicci Chiara , Grafone Tiziana , Tosi Patrizia , Zamagni Elena , Cellini Claudia , Cangini Delia , Tacchetti Paola , Perrone Giulia , Soverini Simona , Martinelli Giovanni , Baccarani Michele , Cavo Michele 
Published: April 2020

Abstract
The chromosome (chr.) 4p16 is involved in one of the alteration most frequently described in Multiple Myeloma (MM) patients at diagnosis, t(4;14). This translocation (tr.) affects the IgH locus on chr.14q32, and a conserved gene cluster region, on chr.4p16: breakpoints on chr.4p16 fall within MMSET coding region, thus allowing the formation of a fusion gene between IgH and MMSET; moreover, as a consequence of the tr., der(14) carries FGFR3, a tyrosine kinase receptor, TACC3, an erythropoietin induced gene, and the IgH 3′ Cα enhancer, while der(4) carries MMSET, a member of the NR-binding SET domain containing gene family and the IgH Eμ enhancer.
In the present study, t(4;14) has been investigated in a series of 63 newly diagnosed MM patients (pts) assigned to receive either single or double autologous transplantation as part of up-front therapy for their malignancy. The frequency and prognostic value of this tr. has been evaluated, as well as the expression of FGFR3 and TACC3 and their possible involvement in MM pathogenesis. To this aim, t(4;14) has been identified by means of RT nested PCR of the IgH/MMSET fusion gene and the expression of FGFR3 and TACC3 was evaluated by Real-Time PCR.
In the cohort analyzed, 17/63 (27%) pts at diagnosis carried t(4;14) and the presence of the fusion gene was confirmed in the last collected sample. On an intent to treat basis, the attainment of stringently defined complete remission (CR) was significantly higher in t(4;14)- as opposed to t(4;14)+ pts (39% vs. 12%, P=0.04). With a median follow-up of 55 months from start of therapy, median EFS was 20 months for pts with IgH-MMSET hybrid transcripts and 31 months for pts without IgH-MMSET (P=0.04). In the t(4;14)+ subgroup of pts, the median FGFR3 expression value resulted significantly higher than in the t(4;14)- subgroup (64.8 vs. 0.8, p =0.0001, Mann-Whitney test). Nevertheless, the over-expression of FGFR3 was observed only in 13 out of 17 t(4;14)+ pts (76.5%). At the opposite, the median TACC3 expression value resulted widely high in MM samples. However, we were not able to evidence a statistically significant difference between the two groups with respect to TACC3 over expression values, which were 16.5 for the t(4;14)+ pts and 14.3 for the t(4;14)- pts (P = 0.7, Mann-Whitney test). The loss of der(14) (harbouring both FGFR3 and TACC3) in a few pts has been already indicated as responsible for the lack of FGFR3 expression. Nevertheless, this event does not seem to affect also TACC3 expression, as it resulted deregulated independently from the presence of t(4;14) in all MM pts evaluated. Thus, as TACC3 deficiency has been associated with a high rate of apoptosis, the wide over-expression of TACC3 observed in our cohort of pts may reflect the general inability to undergo apoptosis, typical of MM neoplastic cells. In conclusion, we confirmed that t(4;14), described in 27% of our series of pts, is associated to poor prognosis. Nor FGFR3, neither TACC3 seemed to be responsible for the worsened outcome of t(4;14)+ pts. This suggest that other genes may represent the target of this tr., while TACC3 may be more widely involved in MM pathogenesis.