CHIC2, 4q12 Deletion (FIP1L1 and PDGFRA Fusion), FISH
Providing diagnostic genetic information for patients with hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD) involving CHIC2 deletion
Establishing the percentage of neoplastic interphase nuclei for patients with HES and SMCD at diagnosis and during treatment
Monitoring response to therapy
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Imatinib mesylate (Gleevec), a small molecule tyrosine kinase inhibitor from the 2-phenylaminopyrimidine class of compounds, has shown activity in the treatment of malignancies that are associated with the constitutive activation of a specific subgroup of tyrosine kinases. A novel tyrosine kinase, generated from fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRA gene, was identified in 9 of 16 patients (56%) with hypereosinophilic syndrome (HES). This fusion results from an approximate 800 kb interstitial chromosomal deletion that includes the cysteine-rich hydrophobic domain 2 (CHIC2) locus at 4q12. FIP1L1-PDGFRA is a constitutively activated tyrosine kinase that transforms hematopoietic cells, and is a therapeutic target for imatinib in a subset of HES patients.
Mast cell disease (MCD) is a clinically heterogeneous disorder wherein accumulation of mast cells (MC) may be limited to the skin (cutaneous mastocytosis) or involve 1 or more extra-cutaneous organs (systemic MCD [SMCD]). SMCD is often associated with eosinophilia (SMCD-eos). We recently tested the therapeutic activity of imatinib in 12 adults with SMCD-eos. In this study, we demonstrated that FIP1L1-PDGFRA is the therapeutic target of imatinib in the specific subset of patients with SMCD-eos. Furthermore, we provided evidence that the CHIC2 deletion is a surrogate marker for the FIP1L1-PDGFRA fusion.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range.
Detection of an abnormal clone is usually associated with hypereosinophilic syndrome or systemic mastocytosis associated with eosinophilia.
The absence of an abnormal clone does not rule out the presence of neoplastic disorder.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test does not rule out cytogenetic or molecular genetic anomalies other than those specifically associated with CHIC2 deletion or insertional translocation.
This method accurately detects deletion of CHIC2 and translocations involving the CHIC2 locus. We investigated a consecutive series of adult patients seen at Mayo Clinic with moderate or severe eosinophilia (median absolute eosinophil count of 4.1 x 10(9)/L, range 1.5-126.8/L). Bone marrow specimens were processed for FISH using standard methods. The FISH methodology was validated in 30 normal bone marrow and peripheral blood controls. Results of this study are in Pardanani A, Brockman SR, Paternoster SF, et al: F1P1L1-PDGFRA fusion: Prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosiniphilia. Blood 104:3038-3045, 2004)
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Pardanani A, Ketterling RP, Brockman SR, et al: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood Nov 1 2003;102(9):3093-3096
2. Pardanani A, Brockman SR, Paternoster SF, et al: F1P1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosiniphilia. Blood 2004;104:3038-3045
3. Cools J, DeAngelo DJ, Gotlib J, et al: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med Mar 2003;348(13):1201-1214