11. ROS1 gene rearrangements in non-small cell lung carcinoma - A new genetic target

Abstract

<h3>Background</h3> Targeted therapies aimed at specific molecular genetic alterations are revolutionising cancer treatment, particularly in non-small cell lung cancer (NSCLC). Driver mutations involving translocation of the <i>ROS1</i> gene have recently been identified in NSCLC and show promise as a target for tyrosine kinase inhibitors. <h3>Aim</h3> To investigate the incidence and clinicopathological features of NSCLC harbouring <i>ROS1</i> rearrangements and the accuracy of IHC compared to FISH at identifying these tumours. Methods: We tested for <i>ROS1</i> translocations using a FISH break-apart probe and immunohistochemistry (IHC) in (1) tissue micro-arrays from a retrospective cohort of 308 early stage adenocarcinomas, (2) a prospective cohort of 23 NSCLC, selected on clinical grounds for mutation testing. <h3>Results</h3> Only 1 of 308 cases was positive by FISH in the retrospective cohort giving a 0.3% incidence of <i>ROS1</i> gene rearrangements. ROS1 IHC was positive in 7 (2.3%) of these cases, including the FISH+ case (sensitivity 100%, specificity 98%). In the prospective cohort, three cases with <i>ROS1</i> rearrangement were identified by FISH (all IHC positive). All 4 cases of ROS1 gene rearrangement identified by FISH occurred in adenocarcinomas that were <i>EGFR</i>-wild-type, ALST-negative, from non-smoking females (age range 33-81 years, mean 59). Two were of Asian ethnicity. <h3>Conclusions</h3> <i>ROS1</i> gene rearrangements occur in a very small percentage of lung adenocarcinomas and are mutually exclusive with EGFR and <i>ALK</i> alterations. Screening with IHC may be a suitable method of reducing the number of cases requiring FISH.