Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics
Por:
Siegel, DH, Cottrell, CE, Streicher, JL, Schilter, KF, Basel, DG, Baselga, E, Burrows, PE, Ciliberto, HM, Vigh-Conrad, KA, Eichenfield, LF, Holland, KE, Hogeling, M, Jensen, JN, Kelly, ME, Kim, W, King, DM, McCuaig, C, Mueller, KA, Pope, E, Powell, J, Price, H, Steiner, JE, Frieden, IJ, Tollefson, MM, Drolet, BA
Publicada:
1 abr 2018
Resumen:
Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.
Filiaciones:
Siegel, DH:
Med Coll Wisconsin, Dept Dermatol & Pediat, Milwaukee, WI 53226 USA
Cottrell, CE:
Nationwide Childrens Hosp, Inst Genom Med, Columbus, OH USA
Streicher, JL:
Childrens Hosp Philadelphia, Dept Dermatol, Philadelphia, PA 19104 USA
Schilter, KF:
Med Coll Wisconsin, Dept Dermatol & Pediat, Milwaukee, WI 53226 USA
Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA
Basel, DG:
Med Coll Wisconsin, Dept Pediat, Div Genet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA
Baselga, E:
Hosp Santa Creu & Sant Pau, Dept Dermatol, Barcelona, Spain
Burrows, PE:
Med Coll Wisconsin, Dept Radiol, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA
Ciliberto, HM:
Univ Iowa, Dept Dermatol, Iowa City, IA USA
Vigh-Conrad, KA:
Washington Univ, Sch Med, Dept Pathol & Immunol, Genom & Pathol Serv, St Louis, MO USA
Eichenfield, LF:
Univ Calif San Diego, Rady Childrens Hosp San Diego, Dept Dermatol, San Diego, CA 92103 USA
Holland, KE:
Med Coll Wisconsin, Dept Dermatol & Pediat, Milwaukee, WI 53226 USA
Hogeling, M:
Univ Calif Los Angeles, Dept Dermatol, Los Angeles, CA USA
Jensen, JN:
Med Coll Wisconsin, Dept Plast Surg, Milwaukee, WI 53226 USA
Kelly, ME:
Akron Childrens Hosp, Dept Pediat, Akron, OH USA
Kim, W:
Loyola Univ Med Ctr, Dept Dermatol, Maywood, IL 60153 USA
King, DM:
Med Coll Wisconsin, Dept Orthoped Surg, Milwaukee, WI 53226 USA
McCuaig, C:
Hosp St Justine, Dept Pediat Dermatol, Montreal, PQ, Canada
Mueller, KA:
Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA
Pope, E:
Hosp Sick Children, Dept Dermatol, Toronto, ON, Canada
Powell, J:
Hosp St Justine, Dept Pediat Dermatol, Montreal, PQ, Canada
Price, H:
Phoenix Childrens Hosp, Dept Dermatol, Phoenix, AZ USA
Steiner, JE:
Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA
Frieden, IJ:
Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA
Tollefson, MM:
Mayo Clin, Dept Dermatol & Pediat, Rochester, MN USA
Drolet, BA:
Med Coll Wisconsin, Dept Dermatol & Pediat, Milwaukee, WI 53226 USA
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