A Mosaic Activating Mutation in<i>AKT1</i>Associated with the Proteus Syndrome

Lindhurst, Marjorie J.; Sapp, Julie C.; Teer, Jamie K.; Johnston, Jennifer J.; Finn, Erin; Peters, K. E.; Turner, Joyce; Cannons, Jennifer L.; Bick, David; Blakemore, Laurel C.; Blumhorst, Catherine; Brockmann, Knut; Calder, Peter; Cherman, Natasha; Deardorff, Matthew A.; Everman, David B.; Golas, Gretchen; Greenstein, Robert M.; Kato, B. Maya; Keppler‐Noreuil, Kim M.; Kuznetsov, Sergei A.; Miyamoto, Richard T.; Newman, Kurt D.; Ng, David; O’Brien, Kevin; Rothenberg, Steven; Schwartzentruber, Douglas J.; Singhal, Virender K.; Tirabosco, Roberto; Upton, Joseph; Wientroub, Shlomo; Zackai, Elaine H.; Hoag, Kimberly; Whitewood-Neal, Tracey; Robey, Pamela Gehron; Schwartzberg, Pamela L.; Darling, Thomas N.; Tosi, Laura L.; Mullikin, James C.; Biesecker, Leslie G.

doi:10.1056/nejmoa1104017

Cited by 796 publications

(620 citation statements)

References 33 publications

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“…We conclude that the mutation exists in both affected and unaffected tissue, but in a higher percentage in affected tissue. It has been observed in other mosaic disorders that the mutation percentage may vary and that mutations can occur even in seemingly unaffected tissue 9, 10…”

Section: Discussionmentioning

confidence: 99%

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Frisk

Grandpeix-Guyodo

Silwerfeldt

et al. 2018

Clinical Case Reports

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Section: Discussionmentioning

confidence: 99%

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Frisk

Grandpeix-Guyodo

Silwerfeldt

et al. 2018

Clinical Case Reports

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“…It may be utilised for the analysis of pathogen populations, such as viruses or bacteria, for the assessment of T-cell diversity 22 , or for detecting rare somatic mutations associated with diseases, such as the Proteus syndrome 23 . Another application is the cost-effective pooled sequencing of multiple individuals.…”

Section: Discussionmentioning

confidence: 99%

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

et al. 2012

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According to the clonal evolution model, tumour growth is driven by competing subclones in somatically evolving cancer cell populations, which gives rise to genetically heterogeneous tumours. Here we present a comparative targeted deep-sequencing approach combined with a customised statistical algorithm, called deepsnV, for detecting and quantifying subclonal single-nucleotide variants in mixed populations. We show in a rigorous experimental assessment that our approach is capable of detecting variants with frequencies as low as 1/10,000 alleles. In selected genomic loci of the TP53 and VHL genes isolated from matched tumour and normal samples of four renal cell carcinoma patients, we detect 24 variants at allele frequencies ranging from 0.0002 to 0.34. moreover, we demonstrate how the allele frequencies of known single-nucleotide polymorphisms can be exploited to detect loss of heterozygosity. our findings demonstrate that genomic diversity is common in renal cell carcinomas and provide quantitative evidence for the clonal evolution model.

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“…For example, Proteus syndrome, a congenital disease involving overgrowth of skin, muscles, fatty tissues, and blood vessels, as well as pulmonary cysts and venous dilatation, is caused by somatic mosaic mutations of AKT1 p.E17K (37). Afflicted individuals are at increased risk for developing benign tumors of the ovary, meninx, and the parotid gland.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

Jung

Kim

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pulmonary sclerosing hemangioma (PSH) is a benign tumor with two cell populations (epithelial and stromal cells), for which genomic profiles remain unknown. We conducted exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3 of 68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Because the AKT1 mutations were not found to cooccur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be the singlemost common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas, including a high rate of AKT1 mutation in PSHs. These genomic features of PSH identified in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors.pulmonary sclerosing hemangioma | whole-exome sequencing | AKT1 mutation | copy number alteration

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A Mosaic Activating Mutation inAKT1Associated with the Proteus Syndrome

Cited by 796 publications

References 33 publications

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

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