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  Oncology
ALK Break Apart FISH Probe Kit   Cat No  CT-PAC009
Lung Cancer Diagnostic Kit              

The ALK FISH probe set is designed to detect rearrangements involving portions of the human ALK gene located on chromosome band 2p23.2. The kit contains two differentially labeled Locus Specific Probes (LSP), one covering the 5’ (start) portion of the ALK gene and some adjacent genomic sequence, the other covering the 3’ (end) part and the neighboring downstream region. The two probes are designed to recognize sequences on both sides of a common breakpoint that is located inside the ALK gene. In addition to revealing breaks, which lead to inversion and translocation of parts of the gene, or its fusion to other genes, the probe set can also be used to identify other ALK aberrations such as deletions or amplifications.

 
 
 ALK Gene

Fluorescence in situ hybridization (FISH) is a powerful technique designed to detect presence or absence, location, integrity and amount of genomic sequences in tissue samples or cells.1-3

The ALK gene codes for anaplastic lymphoma kinase (ALK), also called CD246 (cluster of differentiation 246). ALK is a trans-membrane receptor tyrosine kinase belonging to the insulin receptor superfamily. The biological role of ALK is not yet well understood, and the nature of its natural ligand is still subject of debate. Normal ALK is expressed abundantly in embryonic neural cells and in some parts of the adult brain. It is therefore believed to play a role in the development and function of the central nervous system.4

Abnormal expression of ALK, on the other hand, has been linked to uncontrolled cell growth and survival. Initially discovered in anaplastic large cell lymphoma (ALCL), ALK abnormalities have subsequently been found in a growing number of other malignancies, including B- and T-cell lymphomas, plasmacytoma, neuroblastoma, lung, esophageal, breast, kidney, colon, thyroid and other cancers. Aberrant ALK activation can be the result of gene amplification or of point mutations. However, in the majority of these cancers, ALK expression is caused by chromosomal translocations leading to the production of oncogenic fusion proteins. More than 30 different genes have so far been identified as fusion partners for ALK.5-7

ALK and Lung Cancer 

Lung cancer is the most frequently diagnosed cancer and the leading cause of death from cancer in men worldwide. In women, it is the fourth most frequent and the second most deadly cancer.8 The two main types of lung cancer are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Tobacco smoking is believed to be the cause of most lung cancers, but 10-20% of cases occur in non-smokers. Most lung cancers diagnosed in non-smokers are NSCLC.9

A significant percentage of NSCLC cases harbor ALK gene abnormalities.10 In a particularly common rearrangement, the 3’-portion of the gene, coding for the oncogenic kinase domain, is fused to the 5’-portion of another gene and expressed under the control of the promoter of that gene.11 The most frequent ALK-fusion partner in NSCLC is the EML4 gene, but other fusion partners such as TFG and KIF5B have been described, and more are likely to be discovered.4

Response rates of lung cancer to standard chemotherapy are generally poor. In recent years, however, targeted inhibitors of ALK have been developed for the treatment of ALK-driven cancers. The first FDA-approved ALK-inhibitor is the orally bioavailable small molecule Crizotinib (trade name XALKORI®, Pfizer, Inc.).12 Early trials showed remarkable rates and duration of response to XALKORI® in NSCLC patients with EML4-ALK fusion.13 Clinical trials of ALK inhibitors in other tumor types are in progress.  Presence of the EML4-ALK gene fusion, as detected by FISH, is a strong predictor of the response of a patient’s tumor to these inhibitors. In addition, ALK-positive tumors rarely harbor EGFR, KRAS or ERBB2 mutations and are thus unlikely to benefit from EGFR- or HER2-inhibitor therapy.

ALK kinase can also be detected by immunohistochemistry. However, fusion protein expression is often weak or undetectable, rendering the break-apart FISH assay a more conclusive test for the presence of ALK gene rearrangements.14
 

References

1) O’Connor, C. Nature Education 1:1 (2008).
2) Tsuchiya, KD. Clin. Lab. Med. 31(4): 525-42 (2011).
3) Ried T, et al. Hum Mol Genet. 7(10):1619-26 (1998).
4) Minoo P, Wang HY. Int J Clin Exp Pathol. 5(5):397-410 (2012).
5) Morris SW, et al. Oncogene 14(18):2175-88 (1997).
6) Chiarle R, et al. Nat Rev Cancer 8(1):11-23 (2008).
7) Barreca A, et al. J Mol Endocrinol. 47(1):R11-23 (2011).
8) Jemal A, et al. CA Cancer J Clin. 61(2):69-90 (2011).
9) Thun MJ, et al. PLoS Med. 5(9):e185 (2008).
10) Salido M, et al. J Thorac Oncol. 6(1):21-7 (2011).
11) Soda M, et al. Nature 448(7153):561-6 (2007).
12) Hallberg B, Palmer RH. N Engl J Med. 363(18):1760-2 (2010).
13) Kwak EL, et al. N Engl J Med. 363(18):1693-703 (2010).
14) Sasaki T, et al. Eur J Cancer 46(10):1773-80 (2010).

 

 
   

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