Person:

Fletcher, Christopher

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation1–3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions inactivate larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer.

NUT midline carcinomas (NMC) comprise a group of highly aggressive tumors that have been reported primarily in the head, neck, and mediastinum of younger individuals. These tumors overexpress the nuclear protein in testis (NUT), most commonly due to a chromosomal translocation that fuses the NUT gene on chromosome 15 with the BRD4 gene on chromosome 19. Although the earliest recognized cases were described in the thymus or mediastinum, an extensive survey for NMC among malignant thymic or other mediastinal neoplasms has not been reported. We examined NUT expression in 114 cases of poorly differentiated carcinomas or unclassified mediastinal malignancies using a clinically validated NUT-specific monoclonal antibody. Four of 114 (3.5%) cases showed nuclear NUT expression. A NUT translocation was confirmed by fluorescence in situ hybridization (FISH) in 3 of these cases. These tumors arose in two male and two female adults with a median age of 50 (range 28 to 68). Three of the tumors were originally diagnosed as undifferentiated epithelioid or round cell malignant neoplasms; one tumor contained focal squamous differentiation and was originally diagnosed as a poorly differentiated squamous carcinoma of probable thymic origin. We find that the incidence of NMC within the mediastinum, particularly amongst undifferentiated tumors, is similar to that reported at other anatomic sites. NMC should be considered in the differential diagnosis of any poorly-differentiated epithelioid mediastinal tumor, regardless of age.