Abstract
Fluorescence in situ hybridization (FISH) is currently the gold-standard assay to detect recurrent genomic abnormalities of prognostic significance in multiple myeloma (MM). Since most translocations in MM involve a position effect with heterogeneous breakpoints, we hypothesize that FISH has the potential to miss translocations involving these regions. We evaluated 70 bone marrow samples from patients with plasma cell dyscrasia by FISH and whole-genome mate-pair sequencing (MPseq). Thirty cases (42.9%) displayed at least one instance of discordance between FISH and MPseq for each primary and secondary abnormality evaluated. Nine cases had abnormalities detected by FISH that went undetected by MPseq including 6 tetraploid clones and three cases with missed copy number abnormalities. In contrast, 19 cases had abnormalities detected by MPseq that went undetected by FISH. Seventeen were MYC rearrangements and two were 17p deletions. MPseq identified 36 MYC abnormalities and 17 (50.0% of MYC abnormal group with FISH results) displayed a false negative FISH result. MPseq identified 10 cases (14.3%) with IgL rearrangements, a recent marker of poor outcome, and 10% with abnormalities in genes associated with lenalidomide response or resistance. In summary, MPseq was superior in the characterization of rearrangement complexity and identification of secondary abnormalities demonstrating increased clinical value compared to FISH.
Highlights
Multiple myeloma (MM) is a plasma cell neoplasm (PCN) representing the second most common hematopoietic malignancy and accounts for ~20% of all hematologic cancer related deaths in the United States1
Since many translocations identified in MM involve a position effect (i.e., IGH and mainly with partner chromosome 8q24.21 (MYC)) with heterogeneous breakpoints10,23,24 and some copy number abnormalities (CNA) may be cryptic, we hypothesize that some clinical fluorescence in situ hybridization (FISH) probes used in the characterization of PCNs have a high rate of false negative FISH results
CD138 enriched plasma cells as the preferred methodology in order to identify recurrent primary and secondary genomic abnormalities of prognostic and therapeutic significance in patients with PCNs15. The majority of these laboratories utilize only a limited FISH panel with many focusing on high risk abnormalities defined by the revised International Staging System (R-ISS) including 1q gain, t(4;14), t(14;16) or 17p deletion15
Summary
Multiple myeloma (MM) is a plasma cell neoplasm (PCN) representing the second most common hematopoietic malignancy and accounts for ~20% of all hematologic cancer related deaths in the United States. FISH assays have high sensitivity, are relatively inexpensive compared to NGS techniques and provide input for risk stratification, several limitations exist. They allow for the interrogation of only the regions for which FISH probes are available and multiple FISH probes are needed in order to be comprehensive, with each probe requiring a resourceconsuming validation. Since many translocations identified in MM involve a position effect (i.e., IGH and MYC) with heterogeneous breakpoints and some CNAs may be cryptic, we hypothesize that some clinical FISH probes used in the characterization of PCNs have a high rate of false negative FISH results
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