title: In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression.
abstract: This study analyzed the frequency and clinical significance of t(4;14)(p16;q32) in multiple myeloma (MM) among 208 patients with MM and 52 patients with monoclonal gammopathy of undetermined significance (MGUS); diagnosed between 1994 and 2001. Patients with the translocation were identified using reverse transcription-polymerase chain reaction (RT-PCR) to detect hybrid immunoglobulin heavy chain (IgH)-MMSET transcripts from the der(4) chromosome. We found 31 (14.9%) t(4;14)(+) MM patients and 1 (1.9%) t(4;14)(+) MGUS patient. IgH-MMSET hybrid transcripts were detected in bone marrow (BM) and blood. Breakpoint analysis revealed that 67.7% of t(4;14)(+) patients expressed hybrid transcripts potentially encoding full-length MMSET, whereas the remainder lacked one or more amino terminal exons. Expression of fibroblast growth factor receptor 3 (FGFR3), presumptively dysregulated on der(14), was detected by RT-PCR in only 23 of 31 (74%) patients with t(4;14)(+) MM. Patients lacking FGFR3 expression also lacked detectable der(14) products. Longitudinal analysis of 53 MM patients with multiple BM and blood samples showed that, over time, BM from t(4;14)(+) patients remained positive and that t(4;14)(-) patients did not acquire the translocation. IgH-MMSET hybrid transcripts and FGFR3 transcripts disappeared from blood during response to therapy. No correlation was observed between the occurrence of t(4;14) and known prognostic indicators. However, we find the t(4;14) translocation predicts for poor survival (P =.006; median, 644 days vs 1288 days; hazard ratio [HR], 2.0), even in FGFR3 nonexpressors (P =.003). The presence of t(4;14) is also predictive of poor response to first-line chemotherapy (P =.05). These results indicate a significant clinical impact of the t(4;14) translocation in MM that is independent of FGFR3 expression.
authors.affiliation: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Canada.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maxwell
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Taylor
authors.forename: Loree M
authors.initials: LM
authors.lastname: Larratt
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mant
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000737:chemistry; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D005260:Female; D015870:Gene Expression; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger / Q000032:analysis / Q000097:blood; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014178:Translocation, Genetic
chemical_list: C115494:IgH-MMSET fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3