Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

• Published in: Nature genetics Vol. 44; no. 8; pp. 928 - 933
• Main Authors: Lindhurst, Marjorie J, Parker, Victoria E R, Payne, Felicity, Sapp, Julie C, Rudge, Simon, Harris, Julie, Witkowski, Alison M, Zhang, Qifeng, Groeneveld, Matthijs P, Scott, Carol E, Daly, Allan, Huson, Susan M, Tosi, Laura L, Cunningham, Michael L, Darling, Thomas N, Geer, Joseph, Gucev, Zoran, Sutton, V Reid, Tziotzios, Christos, Dixon, Adrian K, Helliwell, Timothy, O'Rahilly, Stephen, Savage, David B, Wakelam, Michael J O, Barroso, Inês, Biesecker, Leslie G, Semple, Robert K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/68; 631/80/86; 692/699/2743/1530; Adipose tissue; Adipose Tissue - enzymology; Adipose Tissue - pathology; Adipose tissues; Adolescent; Adult; Agriculture; Animal Genetics and Genomics; Archives & records; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedical research; Biomedicine; Bone and Bones - enzymology; Bone and Bones - pathology; Bone surgery; Cancer; Cancer Research; Cell division; Cell growth; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Connective Tissue - enzymology; Connective Tissue - pathology; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; Enzyme Activation - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Health aspects; Human Genetics; Humans; Hyperplasia; Infant; Kinases; letter; Male; Medical research; Middle Aged; Mosaicism; Mutation; Phenotype; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Protein kinases; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Risk factors; Signal Transduction; Syndrome; United States; United Kingdom; Somatic mutation; Enzyme; Transferases; Hyperplasia; 1-Phosphatidylinositol 3-kinase
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2332

Leslie Biesecker and colleagues report an exome sequencing study identifying somatic activating mutations in
PIK3CA
as the cause of a new progressive segmental overgrowth disorder. They identify mutations in
PIK3CA
in ten additional individuals with overlapping syndromes.
The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of
PIK3CA
in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP
3
) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.