Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD–pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD–gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.
All kinds of muscular dystrophies (MDs) are characterized by progressive muscle wasting due to life-long proliferation of precursor cells of myo- (muscle), fibro- (connective tissue), and lipogenic (fat) origin. Despite discovery of many MD genes over the past 25 years, MDs still represent debilitating, incurable diseases, which frequently lead to premature death. Thus, it is imperative to gain novel insights into the underlying MD pathomechanisms. Here, we show that different mouse models for the most common human MDs frequently develop skeletal musculature-associated tumors, presenting as complex sarcomas, consisting of myo-, lipo-, and fibrogenic compartments. Collectively, these tumors are characterized by profound genomic instability such as DNA damage, recurring mutations in cancer genes, and aberrant chromosome copy numbers. We also demonstrate the presence of these cancer-related aberrations in dystrophic muscles from MD mice prior to formation of visible sarcomas. Moreover, we discovered corresponding genomic lesions also in skeletal muscles from human MD patients, as well as stem cells cultured thereof, and show that genomic instability precedes muscle degeneration in MDs. We thus propose that cancer-like genomic instability represents a novel, unifying pathomechanism underlying the entire group of genetically distinct MDs, which will hopefully open new therapeutic avenues.