6q22.1 rearrangement; Receptor Tyrosine Kinase (RTK); Non small cell lung cancer
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.
Fluorescence in situ Hybridization (FISH)
10% neutral buffered formalin fixed paraffin embedded tissue
5 mm^3 fresh tissue or 3.0 mL (min. 2.0 mL) FNA in MPLN RPMI media
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)
Specimen exposed to extreme temperature; Insufficient specimen; Improper fixative
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.
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.