Identification of a Recurrent STRN/ALK Fusion in Thyroid Carcinomas

Abstract

Thyroid carcinoma is the most common endocrine malignant tumor and accounts for 1% of all new malignant diseases. Among all types and subtypes of thyroid cancers that have been described so far, papillary thyroid carcinoma is the most frequent. The standard management treatment of these tumors consists of surgery, followed by radioiodine treatment in case of high risk of relapse. The most aggressive forms are commonly treated by chemotherapy, radiotherapy or experimental drug testing. We recently reported the case of a patient presenting an anaplastic thyroid carcinoma with lung metastases. Fluorescence in situ hybridization analysis allowed us to detect a rearrangement of the anaplastic lymphoma kinase (ALK) gene in both tumors. The patient was treated with crizotinib and presented an excellent drug response. We present here the subsequent investigations carried out to further characterize this genetic alteration and to assess the prevalence of ALK rearrangements in thyroid lesions. High resolution array-comparative genomic hybridization data complemented by RT-PCR and sequencing analyses, allowed us to demonstrate the presence of a STRN/ALK fusion. The STRN/ALK transcript consisted of the fusion between exon 3 of STRN and exon 20 of ALK. Subsequent screening of 75 various thyroid tumors by RT-PCR revealed that 2 out of 29 papillary thyroid carcinomas exhibited the same fusion transcript. None was detected in other types of malignant or benign thyroid lesions analyzed. These findings could pave the way for the development of new targeted therapeutic strategies in the treatment of papillary thyroid carcinomas and point to ALK inhibitors as promising agents that merit rapid evaluation.

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

“…STRN-ALK fusions have been reported most frequently in thyroid carcinoma patients, but were also identified in lung carcinoma and papillary renal cell carcinoma (6,37). Interestingly, similar to this case, thyroid tumors harboring STRN-ALK present with aggressive features, such as extrathyroidal extension and lymph node metastasis (37,38). In this study, seven additional ALK fusion partners were identified, including four novel ALK fusion partners, PPP1R21, SENPF, MAPRE3, and PRKAP1B, which add to the growing list of ALK fusion partners in colorectal carcinoma.…”

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions

“…Using CGP conducted during the course of clinical care, this study focused on PAYA cases of papillary, anaplastic, and medullary thyroid carcinoma originating from a variety of practice settings and identified GAs in 93% of these patients. Moreover, most (90%) of the PAYA patients analyzed harbored CRGAs, alterations for which substantial clinical evidence supports an association with response to targeted therapies in various solid tumors, including thyroid carcinomas .…”

“…In this study, we identified PAYA patients harboring RET , NTRK1 , NTRK3 , and ALK fusions. Chimeric proteins that pair the RET , NTRK1 , NTRK3 , and ALK kinase domains with dimerization domains have been characterized as oncogenic drivers, identified in a variety of tumor types and shown to confer sensitivity to molecularly targeted therapies . RET and NTRK fusions, though initially identified in PTC as the first kinase fusions in solid tumors, have been more frequently targeted in other tumor types .…”

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

“…The STRN-ALK fusion has been previously reported in thyroid cancer, with an increased frequency in poorly differentiated (9%) and anaplastic thyroid cancer (4%) compared to papillary thyroid cancer (1.6%). 42,43 STRN-ALK fusions have been reported in patients with NSCLC, with a recent case report describing a patient with this rare fusion event and resistance to alectinib. 44 This is the first report of STRN-ALK fusions in a cohort of patients treated with EGFR tyrosine kinase inhibitors (TKIs).…”