Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome

Department of Pathology, Boston Children's Hospital, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2012; 90(6):1108-15. DOI: 10.1016/j.ajhg.2012.05.006
Source: PubMed


Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.

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Available from: Margot Elizabeth Bowen, Feb 09, 2014
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    • "The majority of PIK3CA mutations cluster at three hot spots within the protein, two in the helical domain (E542 and E545) and one in the kinase domain (H1047), and cause the constitutive activation of the PI3K/Akt signalling pathway (reviewed in Chalhoub and Baker (2009)). Interestingly, similar mutations, including the common cancer-associated 'hot spot' mutations, have also recently been observed in overgrowth conditions such as megalencephaly syndromes (Lee et al., 2012; Riviere et al., 2012), fibroadipose hyperplasia (Lindhurst et al., 2012) and Congenital Lipomatous Overgrowth with Vascular, Epidermal, and Skeletal anomalies (CLOVES) (Kurek et al., 2012). Cancer-associated PIK3CA mutations are invariably somatic and PIK3CA-driven overgrowth syndromes are not inherited suggesting that PIK3CA mutations are not compatible with germline transmission. "
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    ABSTRACT: The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway regulates many cellular functions including proliferation, migration, survival and protein synthesis. Somatic mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K enzyme, are commonly associated with many human cancers as well as recently being implicated in human overgrowth syndromes. However, it is not clear if such mutations can be inherited through the germline. We have used a novel mouse model with Cre recombinase (Cre)-conditional knock-in of the common H1047R mutation into the endogenous Pik3ca gene. Heterozygous expression of the Pik3ca(H1047R) mutation in the developing mouse embryo resulted in failed 'turning' of the embryo and disrupted vascular remodelling within the embryonic and extraembryonic tissues, leading to lethality prior to E10. As vascular endothelial growth factor A (VEGF-A) signalling was disrupted in these embryos, we used Cre under the control of the Tie2 promoter to target the Pik3ca(H1047R) mutation specifically to endothelial cells. In these embryos turning occurred normally but the vascular remodelling defects and embryonic lethality remained, likely as a result of endothelial hyperproliferation. Our results confirm the lethality associated with heterozygous expression of the Pik3ca(H1047R) mutation during development and likely explain the lack of inherited germline PIK3CA mutations in humans. Copyright © 2015. Published by Elsevier Inc.
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    • "Kurek et al. [3] identified mutations in PIK3CA in six patients with CLOVES syndrome, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. They conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA [3]. Further studies are needed to support these mutations. "
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    ABSTRACT: Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome is a recently delineated disorder that comprises vascular malformations (typically truncal), dysregulated adipose tissue, scoliosis, enlarged bony structures (typically of the legs) without progression, or distorting bony overgrowth. The name CLOVE was subsequently extended to CLOVES to emphasize the association with scoliosis/skeletal and spinal anomalies and seizures/central nervous system malformations. We herein report a very rare case of CLOVES syndrome with the findings of lipomatous overgrowth in the cheek (facial asymmetry), vascular malformation (hemangiomas), epidermal nevi (large port wine stains), and skeletal abnormalities (widened first interdigital space, dystrophia in the nail of the first digit of the right foot, and bilateral hypertrophy of the first digits of the feet).
    10/2014; 2014:845074. DOI:10.1155/2014/845074
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    • "rs121913279). This PIK3CA variant has been previously described in patients with asymmetric overgrowth [Kurek et al., 2012; Lindhurst et al., 2012; Rios et al., 2013], as well as in various cancers [Samuels et al., 2004]. "
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    ABSTRACT: We describe a patient who presented with a localized growth of mature fat tissue, which was surgically removed. MRI imaging identified diffuse increase in visceral adipose tissue. Targeted deep sequencing of the resected tissue uncovered a p.H1047R variant in PIK3CA, which was absent in blood. This report expands the phenotypic spectrum of mosaic PIK3CA mutations. © 2014 Wiley Periodicals, Inc.
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