Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Nature, Journal Year: 2018, Volume and Issue: 558(7711), P. 540 - 546

Published: June 1, 2018

Language: Английский

---

New insights into the generation and role of de novo mutations in health and disease

Genome biology, Journal Year: 2016, Volume and Issue: 17(1)

Published: Nov. 28, 2016

Aside from inheriting half of the genome each our parents, we are born with a small number novel mutations that occurred during gametogenesis and postzygotically. Recent exome sequencing studies parent–offspring trios have provided first insights into distribution these de novo in health disease, pointing to risk factors increase their offspring. De been shown be major cause severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, other developmental diseases. In fact, occurrence generation explains why reproductively lethal continue occur population. also predominantly paternal origin increases advanced age. Here, review recent literature on mutations, covering detection, biological characterization, medical impact.

Language: Английский

---

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

Journal of Clinical Investigation, Journal Year: 2018, Volume and Issue: 128(4), P. 1496 - 1508

Published: Feb. 20, 2018

Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous (AVM).To investigate the pathogenesis sporadic intracranial extracranial VMs in 160 children which known genetic causes had been excluded, we sequenced DNA from affected tissue optimized analysis detection low mutant allele frequency.We discovered multiple mosaic-activating variants 4 genes RAS/MAPK pathway, KRAS, NRAS, BRAF, MAP2K1, a pathway commonly activated cancer responsible germline RAS-opathies. These were more frequent than low-flow VMs. In vitro characterization 2 transgenic zebrafish AVM models recapitulated human phenotype validated alleles. Importantly, treatment AVM-BRAF with BRAF inhibitor vemurafinib restored flow AVM.Our findings uncover major cause different clinical types thereby offer potential personalized medical by repurposing existing licensed therapies.This work was funded or supported grants Butterfly Charity, Wellcome Trust (UK), Medical Research Council UK National Institute Health Research, L'Oreal-Melanoma Alliance, European Council, Human Genome (US).

Language: Английский

---

Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies

American Journal of Medical Genetics Part C Seminars in Medical Genetics, Journal Year: 2016, Volume and Issue: 172(4), P. 402 - 421

Published: Nov. 18, 2016

The phosphatidylinositol‐3‐kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations the PI3K/AKT/mTOR are among most common identified cancer, have been shown to cause a spectrum overgrowth syndromes including PIK3CA‐Related Overgrowth Spectrum, Proteus syndrome, brain conditions. Clinical findings these disorders may be isolated or multiple, sporadic mosaic (adipose, skeletal, muscle, brain, vascular, lymphatic), skin abnormalities (including epidermal nevi, hyper‐, hypopigmented lesions), potential risk tumorigenesis. Key negative regulators PI3K‐AKT include PTEN TSC1/TSC2 germline loss‐of function genes established Hamartoma Tumor Syndrome Tuberous Sclerosis Complex. Mosaic forms conditions lead increased activation PI3K mTOR at affected sites there is phenotypic overlap between All associated with significant morbidity limited options for treatment other than symptomatic therapies surgeries. As dysregulation has implicated several small molecule inhibitors targeting different components under clinical investigation. development brings closer prospect somatic PI3K/AKT/mTOR‐related syndromes. This review describes findings, gene pathogenesis syndromes, presents existing future strategies reduce prevent complications disorders. © 2016 Wiley Periodicals, Inc.

Language: Английский

---

Cancer-Associated PIK3CA Mutations in Overgrowth Disorders

Trends in Molecular Medicine, Journal Year: 2018, Volume and Issue: 24(10), P. 856 - 870

Published: Sept. 6, 2018

Cancer-associated activating PIK3CA mutations, when occurring in isolation during early development, cause a spectrum of rare disorders characterized by asymmetric, and often severe, excessive tissue growth malformations. Tissues are not uniformly affected, and, surprisingly, no excess PIK3CA-associated adult cancers has been described. Evidence that low-dose, repurposed cancer therapies may offer effective precision therapy is beginning to emerge. Mouse models driven endogenous expression pathogenic, mosaic alleles only partly recapitulate the disease phenotype. Although it critical for normal cell survival, role human development poorly characterized. one most commonly mutated genes solid cancers. mutations also found benign overgrowth syndromes, collectively known as PIK3CA-related (PROS). As cancer, PROS arise postzygotically, but unlike these embryonic with their timing location critically influencing resulting Recent evidence indicates phosphoinositide 3-kinase (PI3K) pathway inhibitors undergoing trials can provide PROS. Conversely, highlights gaps our understanding PI3K's embryogenesis development. Here, we summarize current knowledge PROS, evaluate challenges strategies modeling, consider implications paradigm cancer. Thirty years ago this year, 1988, enzyme was identified signal transducer downstream activated surface factor receptors [1Whitman M. et al.Type I phosphatidylinositol kinase makes novel inositol phospholipid, phosphatidylinositol-3-phosphate.Nature. 1988; 332: 644-646Crossref PubMed Scopus (738) Google Scholar]. Its initial identification context viral oncogene immediately implicated PI3K now know encoding p110α catalytic subunit its negative regulator, phosphatase tensin homolog (PTEN), among tumors. It long heterozygous PTEN responsible rare, cancer-prone syndromes hamartoma tumor syndrome (PHTS; see Glossary) [2Hollander M.C. al.PTEN loss continuum common cancers, mouse models.Nat. Rev. Cancer. 2011; 11: 289-301Crossref (351) recently, however, have learned generally caused postzygotic PIK3CA, gene [3Keppler-Noreuil K.M. al.Clinical delineation natural history spectrum.Am. J. Med. Genet. A. 2014; 164: 1713-1733Crossref (191) Collectively (PROS), differ from PHTS important respects: usually all cells, due germline transmission, while occur form, disproportionately some tissues, appear be compatible transmission. A key phenotypic difference lies increased risk PI3K-associated Additional variability arises nature complicates efforts establish experimental models. Nevertheless, such needed better disorder preclinical testing targeted therapies. Study diseases improves fundamental biological mechanisms. Given physiological growth, frequent pathological hyperactivation potentially true too. candidate therapeutics targeting bring hope much recently demonstrated an uncontrolled case series treated p110α-specific inhibitor Alpelisib (BYL719) [4Venot Q. al.Targeted patients syndrome.Nature. 2018; 558: 540-546Crossref (247) Increased awareness thus seems timely. This review summarizes activation outlines unanswered questions, discusses opportunities modeling evaluation The first prototype what Class PI3Ks, which catalyze conversion membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] second messenger PI(3,4,5)P3 (also PIP3). subunits divided into two subclasses – IA IB based on differential usage regulatory subunits. PI3Ks heterodimers three (the product p110α, PIK3CB p110β, or PIK3CD p110δ), tightly bound five PIK3R1 products p85α/p55α/p50α, PIK3R2 p85β, PIK3R3 p55γ; Figure 1). p110β widely expressed, p110δ predominantly leukocytes [5Thorpe L.M. al.PI3K cancer: divergent roles isoforms, modes therapeutic targeting.Nat. 2015; 15: 7-24Crossref (881) signals plasma membrane-associated tyrosine kinases via recruitment p85 tyrosine-phosphorylated receptors/receptor-associated adaptor proteins, direct binding RAS leads acute increases PIP3 degradation PI(3,4)P2, stimulating effector proteins PIP3/PI(3,4)P2-binding domains pleckstrin homology domain. Protein B (AKT) serine/threonine best studied effectors, regulating metabolism, proliferation Scholar, 6Manning B.D. Toker AKT/PKB signaling: navigating network.Cell. 2017; 169: 381-405Abstract Full Text PDF (1824) activity constrained, transient localized generation. Both feedback components several phospholipid phosphatases involved termination. Most suppressor PTEN, converts back PI(4,5)P2 importance exquisite regulation signaling exemplified growing number genetic (Figure linked oncogenesis after discovery, until 2004 somatic were reported [7Samuels Y. al.High frequency cancers.Science. 2004; 304: 554Crossref (2915) Through high-throughput sequencing, PI3K/AKT become recognized 'driver' mechanisms many Pan-cancer analyses Cancer Genome Atlas frequently harboring point more than 12 different types, behind TP53 [8Kandoth C. al.Mutational landscape significance across major types.Nature. 2013; 503: 333-339Crossref (2935) 9Lawrence M.S. al.Discovery saturation analysis 21 tumour 505: 495-501Crossref (2085) Cancers high prevalence include breast (>30%), endometrial bladder (>20%), colorectal carcinoma (>17%), head neck squamous (>15%) 10Millis S.Z. al.Landscape phosphatidylinositol-3-kinase alterations 19 784 diverse tumors.JAMA Oncol. 2016; 2: 1565-1573Crossref (158) 11Zhang al.A Pan-Cancer proteogenomic atlas PI3K/AKT/mTOR alterations.Cancer Cell. 31 (820–832.e3)Abstract (302) amplification overexpression any p110 isoform, mutationally Mutations span entire protein except RAS-binding Over 80% cluster at sites, 'hotspots', namely, glutamates (E) 542 545 helical domain, histidine (H) 1047 near C terminus domain 2). These hotspot variants potent effect enzymatic responses (Table S1 [11Zhang 12Dogruluk T. al.Identification variant-specific functions rapid phenotyping mutations.Cancer Res. 75: 5341-5354Crossref (98) Scholar]). established drivers, also, skin lesions epidermal nevi seborrheic keratoses [13Hafner al.Oncogenic characteristic mutation pattern.Proc. Natl. Acad. Sci. U. S. 2007; 104: 13450-13454Crossref (172) lesions, representing another example mosaicism. More postzygotic, mosaic, forms segmental is, asymmetric affecting parts body [14Lindhurst M.J. al.Mosaic fibroadipose hyperplasia PIK3CA.Nat. 2012; 44: 928-933Crossref (226) 15Rivière J.-B. al.De novo AKT3, related megalencephaly syndromes.Nat. 934-940Crossref (520) 16Kurek K.C. al.Somatic CLOVES syndrome.Am. Hum. 90: 1108-1115Abstract (345) Since then, wide conditions attributed p110α. Many affected patterns previously labeled specific syndromes. fragmented inconsistently applied nomenclature classification fails face intermediate leading proposed designation 'PIK3CA-related spectrum', capture under label reflect etiology severity highly variable, ranging overgrowth, digit, extensive, life-threatening vessels and/or organs 3). conceived anatomically variable admixture overgrown vasculature (capillaries, veins lymphatics) adipose dramatically macroscopically. other tissues organs, including bone, brain, peripheral nerves, liver, skeletal cardiac muscle, 17Mirzaa G. al.PIK3CA-associated developmental exhibit distinct classes distribution.JCI Insight. 1e87623Crossref 18Leiter S.M. al.Hypoinsulinaemic, hypoketotic hypoglycaemia PI3-kinase.Eur. Endocrinol. 177: 175-186Crossref (24) Overgrowth manifests birth, progressive childhood norm. Soft-tissue sometimes persists life, cannot currently predicted. Few reports identity genotyping performed whole tissue. However, detected subcultured dermal fibroblasts Scholar], adipocytes [16Kurek lymphatic endothelial cells [19Boscolo E. al.AKT hyper-phosphorylation associated PI3 K patient malformation.Angiogenesis. 18: 151-162Crossref (78) 20Osborn A.J. al.Activating lymphangiogenic phenotype isolated malformations.Hum. Mol. 24: 926-938Crossref (89) (epithelial) keratinocytes [21Groesser L. al.FGFR3, lichenoid keratosis.Br. Dermatol. 166: 784-788Crossref (27) Hotspot very rarely lymphocyte DNA, even overall burden extensive [17Mirzaa 22Kuentz P. al.Molecular diagnosis (PROS) 162 recommendations testing.Genet. 19: 989-997Abstract (63) Available centers judicious surgical 'debulking' regions, procedures hazardous abnormal vascular anatomy. Surgical radiological blocking blood important. Current clinical practice access services show geographical variation, unmet need targeted, less disfiguring approaches large. dependent initiating 4, Key Figure). profile closely resembles 2), suggested focal rarer non-hotspot causing distributed milder explain full range observed phenotypes, observations biochemical studies suggesting graded [12Dogruluk arising anatomical distributions means large will required address possible genotype–phenotype correlation definitively. concentrated cell-autonomous effects processes migration. sites 50% expected if mutation, contains multiple types origin. raises possibility, still tested, mutation-positive exert growth-promoting adjacent distant cells. could involve cell–cell interactions, paracrine factors, exosomes, extracellular matrix. driving assumed stochastically, therefore probability lineages being should each lineage present embryo time mutation. exhibits apparent skewing pattern mesoderm-derived (e.g., tissue, vasculature, bone) neuroectoderm-derived cephalic connective tissue) prominently macroscopically 5). There macroscopic involvement endoderm-derived structures pancreas, liver), little epithelial beyond keratoses, both neuroectodermal origin [23Sarnat H.B. Flores-Sarnat Genetics neural crest neurocutaneous syndromes.Handbook Clinical Neurology. 1st ed. Elsevier, 2013: 309-314Crossref (8) extremely low blood, contrast variants, infrequently note [15Rivière accounted fate decisions, lineage-specific positive selection PIK3CA-mutant stem dynamics. For instance, lead differentiation oncogene-induced senescence, strong [24Kim J.-S. al.Activation p53-dependent suppression PIK3CA.Mol. Biol. 27: 662-677Crossref (128) Hyperactivation attenuation 'exhaustion' cells' regenerative capacity, phenomenon hematopoietic [25Baumgartner al.An ERK-dependent mechanism prevents exhaustion.Cell Stem 22 (879–892.e6)Abstract (61) affect stemness determination pluripotent (PSCs), subtle influence contributes self-renewal [26Yu J.S. Cui W. Proliferation, survival metabolism: signalling pluripotency determination.Development. 143: 3050-3060Crossref (598) 27Yilmaz al.Defining essential CRISPR–Cas9 screening haploid cells.Nat. Cell 20: 610-619Crossref (62) dose-dependent decisions crosstalk 'stemness' pathways sparse. cell-based permit interrogation vivo. potential particular interest given ability generate mesodermal derivatives, corresponding stress diagnostic undertaken accessible areas rather internal especially frankly enlarged, creating inevitable bias. Apparent tissue-selective nonuniform expression, pancreas liver having times lower mRNA arteries, uterus, [28Carithers L.J. approach high-quality postmortem procurement: GTEx project.Biopreserv. Biobank. 13: 311-319Crossref (444) Moreover, capacity expand part adaptation. Adipose vessels, example, grow later regress energy balance injury, inherent plasticity amplified greater trophic stimulus. systematic sampling needed, ideally single-cell form unbiased view distribution To date, malignancy Wilms (nephroblastoma), embryonal pediatric four around 200 [29Gripp K.W. al.Nephroblastomatosis fourth mutation.Am. 170: 2559-2569Crossref (45) Thus, although none enriched breast) Indeed, mentioned earlier, occurs derivatives 5), ectodermal endodermal epithelia. Neuroectodermal occurrence, any, [10Millis emphasize denoting cancer-associated implies confers selective advantage sufficient initiation maintenance [30Stratton M.R. al.The genome.Nature. 2009; 458: 719-724Crossref (2385) illustrated murine demonstrate Pik3ca require cooperating induce [31Robinson al.Novel target subgroups medulloblastoma.Nature. 488: 43-48Crossref (621) 32Green al.PIK3CAH1047R accelerates enhances KRASG12D-driven lung tumorigenesis.Cancer 5378-5391Crossref (22) 33Van Keymeulen al.Reactivation multipotency oncogenic induces heterogeneity.Nature. 525: 119-123Crossref (227) cellular/tissue likely determinant behavior, within single mammary gland, variant Pik3ca-H1047R dictated [33Van 34Koren multi-lineage tumours.Nature. 114-118Crossref (214) In marked predisposes [35De Santis hyper-proliferation: kidney cysts.Cancers (Basel). 9: 30Crossref (29) breast, endometrial, carcinomas. fact p110α-derived PIP3. Instead, opposes isoform. nuclear phosphatase-independent activities [36Shen W.H. al.Essential maintaining chromosomal integrity.Cell. 128: 157-170Abstract (782) 37Song al.Nuclear regulates APC-CDH1 tumor-suppressive complex manner.Cell. 144: 187-199Abstract (303) unclear. further interesting possibility profiles strengths aberrant risk. Side-by-side comparisons published, baseline appears higher conferred function, results modestly basal contexts [38Horie al.Hepatocyte-specific Pten deficiency steatohepatitis hepatocellular carcinomas.J. Clin. Invest. 113: 1774-1783Crossref (539) 39Papa al.Cancer-associated mutants act dominant-negative manner suppress function.Cell. 157: 595-610Abstr

Language: Английский

---

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

The American Journal of Human Genetics, Journal Year: 2017, Volume and Issue: 100(5), P. 725 - 736

Published: May 1, 2017

To explore the genetic architecture of human overgrowth syndromes and growth control, we performed experimental bioinformatic analyses 710 individuals with (height and/or head circumference ≥+2 SD) intellectual disability (OGID). We identified a causal mutation in 1 14 genes 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result product that is less effective neutralizing negatively charged linker DNA because it reduced net charge, binding protein-protein interactions key residues truncated. Functional network demonstrated epigenetic regulation prominent biological process dysregulated OGID. Mutations six genes—NSD1, EZH2, DNMT3A, CHD8, EED—accounted for 44% (311/710). There was significant overlap between involved OGID 611 regions GWASs be height (p = 6.84 × 10−8), suggesting common variation impacting function influences at population level. Increased cellular hallmark cancer there striking 260 somatically mutated driver 1.75 10−14). However, spectra differ, complex genotype-phenotype relationships. These data reveal insights into control demonstrate exome sequencing high diagnostic yield.

Language: Английский

---

PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis

Nature, Journal Year: 2020, Volume and Issue: 578(7793), P. 166 - 171

Published: Jan. 29, 2020

Language: Английский

---

Genetic Basis and Therapies for Vascular Anomalies

Circulation Research, Journal Year: 2021, Volume and Issue: 129(1), P. 155 - 173

Published: June 24, 2021

Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met factor receptor), VEGF (vascular endothelial factor) A/VEGFR receptor) 2 cascades has led to evaluation tailored strategies with preexisting cancer drugs that interfere these pathways. era theranostics started treatment vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2015-001703-32.

Language: Английский

---

Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies

Circulation Research, Journal Year: 2021, Volume and Issue: 129(1), P. 136 - 154

Published: June 24, 2021

Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial that has extravasated from the capillaries. They provide a trafficking route for cells of immune system, thus critically contributing surveillance. Developmental or functional defects in lymphatic vessels, their obstruction damage, lead accumulation tissues, resulting lymphedema. Here we discuss developmental anomalies called malformations and complex manifest as localized multifocal lesions vasculature, respectively. are rare diseases caused mostly somatic mutations can present with variable symptoms based upon size location composed fluid-filled cisterns channels. Substantial progress been made recently understanding molecular basis pathogenesis through identification genetic causes, combined elucidation underlying mechanisms animal disease models patient-derived endothelial cells. Most solitary cause occur genes encode components oncogenic growth factor signal transduction pathways. This led successful repurposing some targeted cancer therapeutics treatment anomalies. Apart act cell-autonomous drivers these anomalies, current evidence points superimposed paracrine contribute additional targets therapeutic intervention. Here, review advances new strategies on identified

Language: Английский

---

A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations

Orphanet Journal of Rare Diseases, Journal Year: 2021, Volume and Issue: 16(1)

Published: July 8, 2021

Abstract Background PIK3CA -related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result activation PI3K/AKT/mTOR signaling pathway. The goals this review to provide education on underlying mechanism disease for group rare conditions summarize recent advancements understanding of, as well current emerging treatment options disorders. Main body spectrum (PROS), malformations, nonvascular lesions. Somatic activating (predominantly hotspots helical kinase domains PIK3CA, but also other domains), lead hyperactivation PI3K pathway, which results abnormal tissue growth. Diagnosis is complicated variability overlap phenotypes associated with should be performed clinicians required expertise along coordinated care from a multidisciplinary team. Although mosaicism presents challenges confirmation mutations, next-generation sequencing selection have improved detection. Clinical improvement, radiological response, patient-reported outcomes typically used assess response clinical studies patients disorders, objective assessment difficult using imaging (due heterogeneous nature these superimposed upon patient growth development). Despite their limitations, outcome tools may best suited gauge improvement. New therapeutic needed an alternative or supplement standard approaches such surgery sclerotherapy. Currently, there no systemic agents regulatory approval mTOR inhibitor sirolimus has been several years trials off label address symptoms. There under investigation act inhibitors target different components pathway including AKT (miransertib) alpha (alpelisib). Conclusion Management requires approach. Further ongoing targeting highly anticipated.

Language: Английский

---