A 62-year-old man with newly diagnosed multiple myeloma has cytogenetics showing t(4;14)(p16.3;q32). Which of the following correctly identifies the oncogenic mechanism and risk category of this translocation?
- A Juxtaposition of FGFR3 (4p16.3) with the IGH enhancer leads to overexpression of FGFR3, a tyrosine kinase receptor; this is a standard-risk lesion responsive to bortezomib
- B This translocation overexpresses cyclin D1, driving G1-S cell cycle progression and is classified as standard risk in ISS staging
- C t(4;14) causes loss of RB1 by deletion, leading to uncontrolled CDK4/6 activity; classified as intermediate risk
- D Translocation juxtaposes MMSET/NSD2 (a histone methyltransferase at 4p16.3) and FGFR3 with the IGH enhancer, causing NSD2-driven H3K36me2 reprogramming of the myeloma epigenome; this is a high-risk lesion associated with shorter PFS with IMID-only regimens ✓
Explanation
t(4;14) is unique among myeloma translocations in targeting two genes at 4p16.3: FGFR3 (brought under IgH enhancer control, overexpressed in ~75% of cases) and NSD2/MMSET (always dysregulated). NSD2 is a histone methyltransferase catalyzing H3K36 dimethylation (H3K36me2), which reprograms the epigenome toward active transcription of proliferation genes and suppresses H3K27me3-mediated silencing. This makes t(4;14) a high-risk cytogenetic feature in multiple myeloma (per R-ISS); patients benefit from bortezomib-containing induction which partly overcomes this adverse biology. t(11;14) overexpresses cyclin D1 and is standard risk.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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