Fusion of Dynactin 1 (DCTN1) to ALK in Inflammatory Myofibroblastic Tumor.
Xiaoke Wang, Chandra Krishnan, Edward Nguyen, Kevin J Mayer, Jennifer L Oliveira, Joanne E Yi, Ping Yang, Michael J Yaszemski, Avudaiappan Maran, Michele R Erickson-Johnson, Andre M Oliveira. Mayo Clinic, Rochester, MN; Dells Children's Medical Center of Central Texas, Austin; Mayo Medical School, Rochester, MN; Mayo Clinic, Rocheser, MN
Background: Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm that usually occurs in younger patients. Approximately 40-50% of cases show genomic rearrangements of the ALK locus with the formation of fusion genes, most commonly TPM3 and TMP4. Herein, we report the identification of a novel fusion of the cytoskeleton dynactin 1 gene (DCTN1) to ALK in IMT.
Design: Histologic review, immunohistochemical evaluation for ALK (Dako, Carpintera, CA) and cytogenetic G-banding analysis were performed using standard techniques. Fluorescence in situ hybridization (FISH) using a commercially available ALK probe (Vysis Inc., Downers Grove, IL, USA) was performed on metaphase and interphase cells. RNA was extracted from cultured tumor cells using standard protocols. Identification of the ALK partner gene was carried out using 5'-rapid amplified cDNA end (5'-RACE) PCR, and confirmed by specific RT-PCR and direct sequencing in triplicate experiments.
Results: A 7-year old female presented with a posterior neck mass measuring 6 cm in greatest dimension. Histologic and immunohistochemical analysis showed a bland spindle cell neoplasm that weakly expressed ALK in a finely granular cytoplasmic pattern. Cytogenetic studies revealed the following karyotype: 46,XX,der(2)t(2;12)(p23;q11) /46,idem,der(11)t(3;11)(p11;q23). Molecular cytogenetic analysis demonstrated rupture and inversion of the centromeric ALK probe on chromosome 2. 5'-RACE PCR identified the in-frame fusion of the exon 16 of DCTN1 on chromosome 2 to the exon 20 of ALK. Specific RT-PCR and direct sequencing confirmed the fusion of DCTN1-ALK.
Conclusions: In this study, a novel DCTN1-ALK fusion was identified in IMT. DCTN1 encodes for dynactin 1, a highly expressed 150 kD cytoskeleton protein that binds to the microtubule protein dynein. The predicted structure of this novel fusion retains the cytoplasmic associated protein (CAP)-glycine and oligomerization domains of DCTN1, and the tyrosine kinase domain of ALK. The ALK immunostaining pattern is consistent with the predicted structure of the novel chimeric protein.
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 17, Monday Afternoon