Signature OncoChip™ | Multiple Myeloma
and Copy Number Evaluation
Clinical Vignette
Improving detection of aberrations in multiple myeloma***
A 69-year-old male presented with severe bone pain in the spine and ribs precipitated by movement that had worsened over the course of several months. The patient had also experienced progressive fatigue and weight loss of about 15 pounds over the same time interval. Initial workup identified a normocytic anemia with a hemoglobin of 10.1 g/dL. Leukocyte count was 4.2 x 109. Serum creatinine was 1.1 mg/dL, calcium was 11.7 mg/dL, β2 microglobulin was 3.6 mg/L, and albumin was 3.2 g/dL. Serum and urine electrophoresis showed hypergammaglobulinemia, and immunoelectrophoresis detected IgG κ serum Monoclonal protein at a concentration of 3.1 g/dL and 0.9 g/dL, respectively. Radiographic study identified numerous lytic lesions, osteoporosis, and several compression fractures of the spine. Bone marrow aspirate showed 42% plasma cell content and a plasma cell labeling index of 0.4%. Based on the results of these studies, a diagnosis of multiple myeloma was made at stage IIIA on the Durie-Salmon system and stage II on the International Staging System, indicating relatively high risk disease. The pathologist ordered a standard cytogenetic workup of bone marrow chromosomes and a FISH panel targeting 1q21, 8p21, 11q23, 13q14, 14q32 (IGH), and 17p13.1 (TP53) with plans to reflex to a secondary FISH panel of IGH partners if the initial panel indicated likelihood of a translocation. Knowing that standard karyotyping for myeloma is often unsuccessful due to the inability to detect plasma cells and that FISH is limited to identifying aberrations only in the specific targeted regions, the pathologist ordered both the OncoChip™ | Copy Number Evaluation and the OncoChip™ | Multiple Myeloma to be run concurrently with karyotype and FISH. FISH testing and OncoChip testing were both performed on CD138-enriched specimens.
Results of the OncoChip testing were reported on the 5th day after receiving the specimen. The OncoChip™ | Multiple Myeloma panel testing identified aberrations in IGH and WWOX near the MAF gene, consistent with a t(14;16)(q32;q23) juxtaposing IGH and MAF, which would result in dysregulation of the latter.1 This translocation is frequently seen in multiple myeloma and has been associated with shorter overall survival.1 The OncoChip™ | Copy Number Evaluation identified several clinically significant abnormalities including a large deletion on 1p, a complex rearrangement of 10p, and monosomy of chromosome 13. The deletion of chromosome 1p included the CDKN2C and FAF1 gene region that has been associated with adverse overall survival.2 Deletions of chromosome 13, including full monosomy, may be associated with poor prognosis, particularly in the presence of additional cytogenetic abnormalities.1,3 The rearrangement of chromosome 10 is a unique rearrangement for this patient, so despite being a significant abnormality does not have known clinical implications. Initial FISH results were completed on day 6 and identified an IGH rearrangement and loss of one copy of the chromosome 13 probe in 50% of cells. The 1p deletion was not identified because it was not targeted by the initial FISH panel. No further FISH testing was performed because array had identified MAF as the IGH translocation partner. Chromosome results were completed on day 12 after receiving the specimen; 5 cells were available for analysis and were normal.
For this patient, the OncoChip™ | Multiple Myeloma translocation analysis in combination with the OncoChip™ | Copy Number Evaluation provided faster, more detailed results and identified additional aberrations as compared to standard cytogenetics and FISH combined. The results obtained from the OncoChip testing provided critical prognostic information as well as identifying several aberrations for monitoring disease progression.
Figure 1. OncoChip™ | Myeloma plots showing IGH/MAF translocation. The top panel shows an ideogram of chromosome 14 with the p-arm to the left and q-arm to the right. The section of chromosome indicated in red is expanded to show the plot of array CGH data for the 14q32.33 sub-band including part of the IGH gene. The pink highlighted area within the plot indicates a peak delineating the translocation breakpoint within IGH. The blue highlighted areas within the plot indicate a deletion adjacent to the translocation breakpoint. The bottom panel similarly shows an ideogram of chromosome 16 with the region below expanded to show the plot of array CGH data for the 16q23.1 sub-band including part of the WWOX gene, which is adjacent to MAF. The pink highlighted area indicates a peak delineating the translocation breakpoint within WWOX.
Figure 1. OncoChip™ | Copy Number Evaluation showing prognostically significant aberrations. The top panel shows an ideogram of chromosome 1 with the p-arm to the left and q-arm to the right. The section of chromosome indicated in red is expanded to show the plot of array CGH data for the 1p12 sub-band through the 1p terminus. The blue highlighted area within the plot indicates the partial deletion of 1p. The bottom panel similarly shows an ideogram of chromosome 13 with the region below expanded to show the plot of array CGH data for the q-arm. The blue highlighted area within the plot indicates deletion of the entire chromosome or monosomy 13. Note the degree of downward shift (log ratio) differs for the two deletions, likely indicating clonality (presence of a subset of cells with monosomy 13 but not the deletion of 1p).
References:
- Fonseca et al. 2004. Cancer Res. 64:1546-58.
- Walker et al. 2010. Blood. 116:e56-65.
- Munshi et al. 2011. Blood. 117:4696-4700.
*** This vignette is based upon a real patient, however specific details have been changed to demonstrate utility of the platform and protect patient privacy.