Signature OncoChip™ | B-cell ALL Panel 1
and Copy Number Evaluation
Clinical Vignette
Determining prognosis in acute lymphoblastic leukemia***
A 52-year-old female presented with fatigue, unexplained weight loss, intermittent recurrent fever, and enlarged lymph nodes. Initial testing indicated elevated leukocyte count and thrombocytopenia. Subsequent workup on bone marrow aspirate identified an increased level of circulating blasts, indicating ALL. Additional testing included immunophenotyping, which suggested a B-cell disorder, and pathology consultation, which identified atypical lymphoblasts, confirming that B-cell ALL was the likely diagnosis. The pathologist ordered the OncoChip™ | B-cell ALL Panel 1 in combination with the OncoChip™ | Copy Number Evaluation, knowing that these tests assess for the most common prognostically important aberrations in B-cell ALL, while providing a faster and more precise answer than standard karyotyping and covering a broad spectrum of aberrations in comparison to FISH panels.4
Results of the OncoChip testing were reported on the 5th day after receiving the specimen. The OncoChip™ | B-cell ALL Panel 1 testing identified aberrations in the BCR andABL1 genes, suggesting a t(9;22)(q34;q11.2) creating a fusion between BCR and ABL1. This translocation is frequently seen in adults with ALL and is considered a significant, adverse prognostic factor.1 The OncoChip™ | Copy Number Evaluation identified an additional 10 abnormalities of likely clinical significance but of unknown prognosis; all but one of these aberrations were significantly below the resolution of standard karyotyping, and therefore would not have been identified by routine cytogenetic studies.5 The alterations identified by the OncoChip™ | Copy Number Evaluation included a 230 kilobase deletion of the IKZF1 gene, which has been associated with significant adverse prognosis in BCR/ABL1 positive and negative patients, and a 375 kilobase deletion of the CDKN2A and CDKN2B genes, which is associated with a similarly adverse prognosis.1-3 Allogenic bone marrow transplantation (BMT) is considered one of the few treatment options for post-remission patients with high-risk B-cell ALL, whereas it may not be considered appropriate for patients with better prognostic indicators.3
For this patient, the OncoChip™ | B-cell ALL Panel 1 in combination with the OncoChip™ | Copy Number Evaluation provided cytogenetics results in a more timely fashion than standard cytogenetics would be able to, while also providing key prognostic information not detectable by standard cytogenetics and currently available FISH panels. As a result, the clinician was able to provide more specific prognostic information to the patient and design post-remission therapy specifically tailored to minimize the risk of relapse.
Figure 1. OncoChip™ | B-cell ALL Panel 1 plots showing BCR/ABL1 translocation.The top panel shows an ideogram of chromosome 9 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 9q34.12 sub-band including ABL1. The pink highlighted area within the plot indicates a peak delineating the translocation breakpoint within ABL1. The bottom panel similarly shows an ideogram of chromosome 22 with the region below expanded to show the plot of array CGH data for the 22q11.23 sub-band including BCR. The pink highlighted area indicates a peak delineating the translocation breakpoint within BCR.
Figure 2. OncoChip™ | Copy Number Evaluation showing submicroscopic, prognostically significant deletions. The top panel shows an ideogram of chromosome 7 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 7p12.2 sub-band including IKZF1. The blue highlighted area within the plot indicates a submicroscopic deletion of IKZF1. The bottom panel similarly shows an ideogram of chromosome 9 with the region below expanded to show the plot of array CGH data for the 9p21.3 sub-band including CDKN2A and CDKN2B. The blue highlighted area within the plot indicates a submicroscopic deletion involving these two genes.
References:
- Iacobucci et al. Blood. 2009 Sep 3;114(10):2159-67.
- Mullighan et al. 2009. NEJM 360:470-480.
- Nahi et al. 2008. Haematologica 93:1734-8.
- Schultz et al. 2007. Blood. 109:926-35
- Smeets 2004. Clin Biochem. 37:439-46.
* As of the date of publishing (01/12/2011) five of the translocations targeted by this assay have been validated according to Signature Genomics’ standard validation procedures.
** This assay is not designed to detect low level mosaicism.
*** This vignette is based upon a real patient, however specific details have been changed to demonstrate utility of the platform and protect patient privacy.