Anaplastic lymphoma kinase (ALK) in rhabdomyosarcoma.

Abstract

9530 Background: Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma that occurs predominantly in children. Despite the use of multi-agent chemotherapy, survival for patients with alveolar histology (ARMS), metastatic and recurrent disease remains poor. Moreover, the intensive treatment regimens result in a high rate of adverse effects. This urges the development of new therapeutic strategies in RMS. ALK inhibitors are currently available for clinical trials. The aim of this study is to investigate ALK as a potential therapeutic target in RMS, with emphasis on protein expression and the underlying genomic aberrations. Methods: Paraffin-embedded RMS tissue samples were collected on tissue microarrays. ALK protein expression was evaluated by immunohistochemistry (ALK1, DAKO). A semiquantitative scoring system was used in which staining was scored negative “0”, and weak “1” or strong “2” when present in at least 10% of the tumor cells. ALK gene copy number and presence of ALK translocation were determined by in situ hybridization. Copy number was divided into normal (0-4 copies), gain (5-10 copies), or amplification (>10 copies) with a cut-off at 10% of the nuclei. LAF (2q11) was used as a reference probe for chromosome 2 aberrations. Results: A total of 107 primary RMS tumors were evaluated (83 embryonal (ERMS) and 24 ARMS). Strong cytoplasmic ALK protein expression was observed more frequently in ARMS than in ERMS (90.9% versus 35.8%, p<0.001). ALK gene copy number gain was detected in the vast majority of ARMS (overall 59.6%; ARMS 90.0%, ERMS 52.1%, p=0.002), and one amplification was identified (ARMS). A significant correlation was observed between ALK copy number gain and strong ALK protein expression (p<0.001). In ERMS cases with ALK gain evaluable for LAF copy number analysis (N=31), ALK/LAF ratio (range 1.10-2.72) was 1.5-2 in 54.8%, and >2 in 12.9%. In ARMS (N=16), ALK/LAF ratio (range 0.95-2.18) was 1.5-2 in 25%, and >2 in 18,75%. No ALK translocations were identified. Conclusions: This study reveals that ALK is a promising target for future treatment of RMS patients. Copy number gains appeared to be one of the underlying mechanisms for ALK protein expression. Further insight into additional genetic aberrations should be subject of future research.