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ROS1 6q22.1 rearrangement by Fluorescent in situ Hybridization

Test Code

FP ROS1

Test Synonyms

6q22.1 rearrangement; Receptor Tyrosine Kinase (RTK); Non small cell lung cancer

Associations

ROS1 is a receptor tyrosine kinase (RTK) of the insulin receptor family. Chromosomal rearrangements involving the ROS1 gene, on chromosome 6q22, were originally described in glioblastomas (e.g., FIG-ROS1). More recently, ROS1 fusions were identified as a potential "driver" mutation in non-small cell lung cancer.

Approximately 2% of lung tumors harbor ROS1 fusions. Like ALK fusions, ROS1 fusions are more commonly found in light smokers (<10 pack years) and/or never-smokers. ROS1 fusions are also associated with younger age and adenocarcinomas. In preclinical models, ROS1 fusions are associated with sensitivity to tyrosine kinase inhibitors that have 'off-target' activity against ROS1, such as crizotinib. ROS1 rearrangements are non-overlapping with other oncogenic mutations found in Non-Small Cell Lung Cancer (NSCLC) (e.g., EGFR mutations, KRAS mutations, ALK fusions, etc.). Several different ROS1 rearrangement partners, including SLC34A2-ROS1, CD74-ROS1, EZR-ROS1, TPM3-ROS1, and SDC4-ROS1 have been described in NSCLC. FISH testing is not able to discern which particular ROS1 fusion is found in a clinical sample.

Methodology

Fluorescence in situ Hybridization (FISH)

Turnaround Time

3-5 days

Specimen Requirements

FFPE tissue is acceptable for FISH analysis. Preferred fixative is 10% neutral buffered formalin. Tissues preserved in B5 fixative or decalcified are usually not suitable for FISH. Tumor sections cut 3-5 µm thick and mounted on positively charged organosilane coated (silanized) slides work well. Request several unstained sections (two for each probe) and one H&E stained slide

Specimen Stability
Stable indefinitely when stored at 20°C to 25°C
Storage & Handling

4°C to 25°C during transit, but specimens may be transported on refrigerated gel packs. Do not allow the gel pack to come in contact with the specimen. Do not freeze. Extreme temperatures should be avoided.

Causes for Rejection

Specimen exposed to extreme temperature; Insufficient specimen; Improper fixative

Reference Range

FISH results indicate whether rearrangement is present or absent.
In a normal cell, two fusion (red/green fused) signals will be seen.
In a cell with a translocation involving ROS1, one red and one green signal will be seen along with one fusion signal.

Description

The LSI dual break-apart rearrangement probe contains two differently labelled probes on either sides of the breakpoint of the ROS1 gene. ROS1 has multiple fusion partners including but not limited to CCDC6, CD74, EZR, KDELR2, LRIG3, SDC4, SLC34A2, and TPM3 in NSCLC.

References
  1. Lovly, C., L. Horn, W. Pao. (2015) ROS1 in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/ros1/ (Updated November 17).
  2. Shaw, A,T,, Ou, S.H., et. al.(2014)  Crizotinib in ROS1-Rearranged Non-Small_Cell Lung Cancer. The New England Journal of Medicine. 2014 Nov. 371 (21): 1963-1971
  3. Bubendorf, L., Büttner, R., Al-Dayel, F. et al. Testing for ROS1 in non-small cell lung cancer: a review with recommendations. Virchows Arch (2016) 469: 489
  4. Shaw, A.T., Camidge, D.R., et. al. (2012). Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Journal of Clinical Oncology 30, 7508-7508
  5. Kurtis D. Davies, Anh T. Le, et. al. (2012). Identifying and Targeting ROS1 Gene Fusions in Non–Small Cell Lung Cancer. Clin Cancer Res September (18) (17) 4570-4579