Ros1 Rearrangements and Copy Number Alterations in Nsclc Patients: High Frequency of Ros1 Deletions

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ABSTRACT Aim: Recently, c-ros oncogene 1, receptor tyrosine kinase (ROS1, 6q22) has been identified as a driver oncogene in non-small-cell lung carcinomas (NSCLC). Patients carrying ROS1 translocations are candidates to targeted therapy with crizotinib®. We aimed to determine the prevalence, patterns and fusion partners in ROS1-rearranged NSCLC samples and to characterize ROS1 copy number alterations (CNAs) by fluorescence in situ hybridization (FISH). Methods: A total of 216 NSCLC patients (median age 64 years, 66% males, 51% smokers, 73% adenocarcinomas (ADC), 35% stage 4), were screened for ROS1 abnormalities using a break-apart FISH probe (Abbott Molecular). To characterize ROS1 partners, clones from Human 32K BAC Re-Array Library were used to develop CD74, SLC34A2 and EZR probes. Immunohistochemistry (IHC) with ROS1 D4D6 antibody (Cell Signalling Technology) was also performed in ROS1-translocated cases. Correlation with clinico-pathologic information was investigated. Results: Four samples were ROS1 translocated (1.9%): three showed deletion of the non-translocated allele and one had a 5'ROS1 deletion. One harbored a SLC34A2-ROS1 fusion and another a CD74-ROS1. No fusion partner was identified in the other two samples. All cases were positive for ROS1 IHC staining, three presenting a cytoplasmic pattern and one with membranous pattern. ROS1-translocated tumors were ADC, all EGFR, KRAS, and ALK wt. We observed an association with non-smoking habit (P=0.036). Regarding CNAs in ROS1 non-rearranged cases, 43.5% had gains (3-6 copies) and 26.4% had deletions. Conclusions: We confirm the low prevalence of ROS1-translocated lung ADC in a Spanish population. Moreover, our study reveals a significant frequency of ROS1 deletion as a potentially relevant aberration, also in ROS1-translocated patients. Disclosure: All authors have declared no conflicts of interest.