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ALK 2p23 rearrangement by FISH

Test Code

F ALK; FP ALK

Test Synonyms

2p23 rearrangement; EML4-ALK; Non small cell lung cancer

Associations

The FDA has approved Crizotinib (Xalkori) for treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive. The ALK Break-Apart FISH Probe Kit detects rearrangement of the anaplastic lymphoma kinase (ALK) gene in NSCLC. Up to 5% of non-squamous NSCLC carry ALK gene rearrangements. Patients negative for EGFR mutations benefit minimally from chemotherapy and are resistant to TKI's. Crizotinib blocks certain kinases including those produced by abnormal ALK gene rearrangement.

A retrospective analysis by Shaw et al, published in Lancet Oncology, showed that ALK-positive NSCLC patients treated with Crizotinib did have improved, two-year survival compared with that of Crizotinib-naive controls.

Methodology

Fluorescence in situ Hybridization (FISH)

Turnaround Time

3-5 days

Specimen Requirements

F ALK
2.0 mL (min. 1.0 mL) peripheral blood in sodium heparin preferred, EDTA accepted
1.0 mL (min. 0.5 mL) bone marrow in sodium heparin preferred, EDTA accepted
5 mm^3 fresh tissue or 3.0 mL (min. 2.0 mL) FNA in MPLN RPMI media

FP ALK
10% neutral buffered formalin fixed paraffin embedded tissue

Specimen Stability
Peripheral blood and bone marrow stable at 18-25°C for 72 hours
Fresh tissue or FNA stable at 2-8°C for 72 hours
FFPE stable indefinitely
Storage & Handling

Whole blood and bone marrow, ship ambient
Fresh tissue, FNA or paraffin embedded tissue, ship in a Styrofoam container with a cool/refrigerated pack (Do not allow cool pack to directly contact sample)

Causes for Rejection

Clotted specimen; Specimen exposed to extreme temperature; Anticoagulant toxic to cells; Insufficient number of cells; Improper fixative

Reference Range

FISH results indicate whether rearrangement is present or absent.
In a normal cell, two yellow (orange/green fused) signals will be seen.
In a cell with a translocation involving ALK, one orange and one green signal will be seen along with one yellow signal.

Description

The LSI dual break-apart rearragement probe contains two differently labelled probes on either sides of the breakpoint of the ALK gene. ALK has multiple fusion partners including NPM in anaplastic large cell lymphoma and EML4 in non small cell lung cancer.
EML4/ALK fusions are the result of paracentric inversions involving the short arm of chromosome 2. The breakpoints of the inversions are within the EML4 locus (2p21) and the ALK locus (2p23).

References
  1. Soda et al. (2007). Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566
  2. Rodig et al.(2009) Unique clinicopathologic features characterize ALK-Rearranged Lung Adenocarcinoma in Western Population. Clin Cancer Res 15:5216-5223
  3. Shaw et al. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK, JCO 26:4247-4253
  4. Patel Ankita et al. (2007). Cancer Genetics and Cytogenetics. 176:107-114.
  5. Onciu M et al. (2003). ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Am J Clin Pathol. 120(4):617.
  6. Liang X et al. (2004). Assessment of t(2;5)(p23;q35) translocations and variants in pediatric ALK+ anaplastic large cell lymphoma. Am J Clin Pathol. 121(4):496.