title: DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies.
abstract: 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.
authors.affiliation: Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Schmidt
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Uddin
authors.forename: Sandra
authors.initials: S
authors.lastname: Dysek
authors.forename: Karin
authors.initials: K
authors.lastname: Moser-Thier
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Harald
authors.initials: H
authors.lastname: Höger
authors.forename: Inge M
authors.initials: IM
authors.lastname: Ambros
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D055028:Comparative Genomic Hybridization; D004249:DNA Damage; D004195:Disease Models, Animal; D000073939:Dysferlin; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology*; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics*
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D016189:Dystrophin; D008565:Membrane Proteins; D009124:Muscle Proteins; C085339:apo-dystrophin 1; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; D002154:Calpain; C491373:Capn3 protein, mouse