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When, where and which PIK3CA mutations are pathogenic in congenital disorders

Subjects

Abstract

PIK3CA encodes the class I PI3Kα isoform and is frequently mutated in cancer. Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with frequent vascular involvement. In PROS, PIK3CA mutations arise postzygotically, during embryonic development, leading to a mosaic body pattern distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favoring some mesoderm-derived and ectoderm-derived tissues is observed but not understood. Here, we summarize our current knowledge of the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias, and extrinsic factors, which refers to environmental modifiers. We also include a section on PIK3CA-related vascular malformations given that the vasculature is frequently affected in PROS. Increasing our biological understanding of PIK3CA mutations in PROS will contribute toward unraveling the onset and progression of these conditions and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insights into one will also inform about the other.

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Fig. 1: Classification of PROS disorders.
Fig. 2: Intrinsic and extrinsic factors that define PIK3CA-related pathogenesis in PROS.
Fig. 3: PIK3CA variants in PROS.

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Acknowledgements

We thank CERCA Programme/Generalitat de Catalunya and and the Josep Carreras Foundation for institutional support. M.G.’s laboratory in the context of PI3K-related vascular malformations is supported by the research grants from the Spanish Ministry of Science and Innovation (PID2020-116184RB-110), PTEN RESEARCH Foundation (BRR-17-001/IJC-21-001) and La Caixa Foundation (LCF/PR/PR16/51110035 and LCF/PR/HR19/52160023); A.A.-U. and M.G. are recipients of a CLOVES syndrome community research grant. We thank S. D. Castillo and T. Mäkinen for their valuable feedback. We apologize to the many authors whose primary papers could not be cited owing to space constraints.

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A.A.-U. and M.G. wrote the manuscript and created the figures.

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Correspondence to Ana Angulo-Urarte or Mariona Graupera.

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M.G. had a research agreement with Merck & Co. and Venthera to test their inhibitors of the PI3K pathway in vascular malformations.

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Nature Cardiovascular Research thanks Guillaume Canaud, Victor Martinez-Glez and Len Stephens for their contribution to the peer review of this work.

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Angulo-Urarte, A., Graupera, M. When, where and which PIK3CA mutations are pathogenic in congenital disorders. Nat Cardiovasc Res 1, 700–714 (2022). https://doi.org/10.1038/s44161-022-00107-8

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