Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3CA
Cytogenetic location: 3q26.32 Genomic coordinates (GRCh38): 3:179,148,126-179,240,093 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.32 | Breast cancer, somatic | 114480 | 3 | |
| Cerebral cavernous malformations 4, somatic | 619538 | 3 | ||
| CLAPO syndrome, somatic | 613089 | 3 | ||
| CLOVE syndrome, somatic | 612918 | 3 | ||
| Colorectal cancer, somatic | 114500 | 3 | ||
| Cowden syndrome 5 | 615108 | 3 | ||
| Gastric cancer, somatic | 613659 | 3 | ||
| Hemifacial myohyperplasia, somatic | 606733 | 3 | ||
| Hepatocellular carcinoma, somatic | 114550 | 3 | ||
| Keratosis, seborrheic, somatic | 182000 | 3 | ||
| Macrodactyly, somatic | 155500 | 3 | ||
| Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic | 602501 | 3 | ||
| Nevus, epidermal, somatic | 162900 | 3 | ||
| Nonsmall cell lung cancer, somatic | 211980 | 3 | ||
| Ovarian cancer, somatic | 167000 | 3 |
Bovine phosphatidylinositol 3-kinase (EC 2.7.1.137) is composed of 85-kD (171833) and 110-kD subunits. The 85-kD subunit lacks PI3-kinase activity and acts as an adaptor, coupling the 110-kD subunit (p110) to activated protein tyrosine kinases. Hiles et al. (1992) found that the bovine cDNA for p110 predicts a 1,068-amino acid protein related to a protein which in S. cerevisiae is involved in the sorting of proteins to the vacuole.
Volinia et al. (1994) cloned the cDNA for the human p110 subunit (PIK3CA) and found that it encodes a protein 99% identical to the bovine p110 enzyme.
See also PIK3CG (601232) and PIK3CD (602839), the genes encoding the p110-gamma and p110-delta polypeptides, respectively.
By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Volinia et al. (1994) mapped the PIK3CA gene to 3q26.3.
Crystal Structure
Miled et al. (2007) used crystallographic and biochemical approaches to gain insight into activating mutations in 2 noncatalytic p100-alpha domains--the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110-alpha in a complex with the p85-alpha (171833) inter-Src homology 2 (inter-SH2) domains shows that the oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. The authors also examined helical domain mutations and found that the glu545-to-lys (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. Miled et al. (2007) concluded that their studies extended understanding of the architecture of the phosphatidylinositol 3-kinases and provided insight into how 2 classes of mutations that cause a gain of function can lead to cancer.
Huang et al. (2007) reported a 3.0-angstrom resolution structure of a complex between p110-alpha and a polypeptide containing the p110-alpha-binding domains of p85-alpha, a protein required for its enzymatic activity. The structure showed that many of the cancer-associated mutations occur at residues lying at the interfaces between p110-alpha and p85-alpha or between the kinase domain of p110-alpha and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. Huang et al. (2007) concluded that, in addition to providing new insights about the structure of PI3K-alpha, these results suggested specific mechanisms for the effect of oncogenic mutations in p110-alpha and p85-alpha.
Hiles et al. (1992) found that bovine p110 was catalytically active only when complexed with p85-alpha in COS-1 cells.
The tumor suppressor PTEN (601728) inhibits cell growth through multiple mechanisms. Furnari et al. (1998) demonstrated that PTEN can dephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, is required for translocation of protein kinase B (AKT1, PKB; 164730) to the cell membrane, where it is phosphorylated and activated by upstream kinases. Weng et al. (2001) demonstrated increased PTEN-mediated cell death of MCF-7 breast cancer cells cultured in low levels of growth factors. The caspase-9 (602234)-specific inhibitor ZVAD blocked PTEN-induced cell death without altering the effect of PTEN on cell cycle distribution. Overexpression of dominant-negative Akt induced more cell death but had less effect on the cell cycle than overexpression of PTEN. The authors suggested that the apoptotic MCF-7 cells induced by the overexpression of PTEN were not derived from G1-arrested cells. They further hypothesized that the effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway, whereas PTEN-mediated cell cycle arrests depend on both PIK3CA/AKT1-dependent and -independent pathways.
Niswender et al. (2001) demonstrated that systemic administration of leptin (164160) in rat activates the enzyme phosphatidylinositol 3-hydroxykinase in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol 3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake.
Shi et al. (2003) reported that selection of the future axon among neurites of a cultured rat hippocampal neuron required the activity of PI3K, as well as atypical protein kinase C (aPKC; see 176982). The PI3K activity, which was highly localized to the tip of the newly specified axon of stage-3 neurons, was essential for the proper subcellular localization of Par3 (606745) Polarized distribution of not only Par3, but also of Par6 (604784), was important for axon formation; ectopic expression of Par6 or Par3, or just the N terminus of Par3, left neurons with no axon specified. The authors concluded that neuronal polarity is likely to be controlled by the PAR3/PAR6/aPKC complex and the PI3K signaling pathway, both of which serve evolutionarily conserved roles in specifying cell polarity.
Cell size is strongly dependent on ribosome biogenesis, which is controlled by RNA polymerase I (see 602000). The activity of this polymerase is modulated by a complex of proteins, including UBTF (600673). From experiments with mouse embryonic fibroblasts, Drakas et al. (2004) presented evidence that a nuclear complex forms between IRS1 (147545), UBTF, and PI3K, leading to the serine phosphorylation of UBF1 and regulation of rRNA synthesis.
High NaCl causes DNA double-strand breaks and activates the transcription factor TONEBP (NFAT5; 604708) via ATM (607585), resulting in increased transcription of protective genes, including those involved in accumulation of compatible organic osmolytes. Irarrazabal et al. (2006) found that PI3K activity was necessary for high NaCl- and ionizing radiation-induced activation of ATM.
Using an array of pharmacologic PI3K inhibitors, Knight et al. (2006) identified p110-alpha as the primary insulin-responsive PI3K in cultured mouse adipocytes and myotubes. p110-beta (PIK3CB; 602925) was dispensable but set a phenotypic threshold for p110-alpha activity. Compounds targeting p110-alpha blocked the acute effects of insulin (176730) challenge in fasted mice, whereas a p110-beta inhibitor had no effect.
Gymnopoulos et al. (2007) performed biologic and biochemical analysis of 15 rare cancer-derived PIK3CA mutants, 14 of which demonstrated gain of function. The gain-of-function mutations mapped to 3 separate functional domains (C2, helical, and kinase) on a partial structural model, suggesting that each type induces a gain of function by a different molecular mechanism.
Graupera et al. (2008) showed that of the PI3 kinases in mice, only p110-alpha activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110-alpha led to embryonic lethality at midgestation because of severe defects in angiogenic sprouting and vascular remodeling. p110-alpha exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA (165390). p110-alpha activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands such as vascular endothelial growth factor (VEGFA; 192240). In contrast, p110-beta in endothelial cells signals downstream of G protein-coupled receptor ligands such as SDF1-alpha (602352), whereas p110-delta is expressed at a low level and contributes only minimally to P13K activity in endothelial cells. Graupera et al. (2008) concluded that their results provided the first in vivo evidence for p110 isoform selectivity in endothelial P13K signaling during angiogenesis.
Kalaany and Sabatini (2009) showed that certain human cancer cell lines, when grown as tumor xenografts in mice, are highly sensitive to the antigrowth effects of dietary restriction, whereas others are resistant. Cancer cell lines that form dietary restriction-resistant tumors carry mutations that cause constitutive activation of the PI3K pathway and in culture proliferate in the absence of insulin or insulin-like growth factor-1 (IGF1; 147440). Substitution of an activated mutant allele of PIK3CA with wildtype PIK3CA in otherwise isogenic cancer cells, or the restoration of PTEN (601728) expression in a PTEN-null cancer cell line, was sufficient to convert a dietary restriction-resistant tumor into one that was dietary restriction-sensitive. Dietary restriction did not affect a PTEN-null mouse model of prostate cancer, but it significantly decreased tumor burden in a mouse model of lung cancer lacking constitutive PI3K signaling. Thus, Kalaany and Sabatini (2009) concluded that the PI3K pathway is an important determinant of the sensitivity of tumors to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies. Kalaany and Sabatini (2009) also found that overexpression of FOXO1 (136533) sensitizes tumors to dietary restriction.
Gustin et al. (2009) found that nontumorigenic human breast epithelial cells with knockin PIK3CA mutations exhibited EGF (131530)- and MTOR (601231)-independent proliferation associated with AKT, ERK, and GSK3B (605004) phosphorylation. Conversely, GSK3B inhibitors selectively decreased proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations and caused a decrease in the GSK3B target gene cyclin D1 (CCND1; 168461). Treatment of nude mice with lithium, a GSK3B inhibitor, inhibited the growth of xenografts of human colon cancer cells with mutant PIK3CA, but not human colon cancer cells expressing wildtype PIK3CA. Gustin et al. (2009) proposed that GSK3B is an important effector of mutant PIK3CA and that lithium has selective antineoplastic properties against cancers with PIK3CA mutations.
Lindhurst et al. (2012) assessed PI3K activity in dermal fibroblasts from 3 individuals with a syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone by applying a mass spectroscopy assay for PIP3 before and after stimulation of cells with EGF. PIP3 levels were 2 times higher in affected cells relative to unaffected cells at baseline and in response to EGF stimulation, and basal PIP3 levels in affected cells were indistinguishable from those in control cells after stimulation. Basal hyperphosphorylation of downstream AKT and p70 S6 kinases were detected in cells with mutant PIK3CA. No signal amplification or induction of phosphorylation was observed in affected cells, reflecting the fact that the signaling cascade is already at maximum stimulation capacity in these cells. There was no increase in signaling through the MEK extracellular-regulated kinase (ERK) pathway. Lindhurst et al. (2012) concluded that these affected individuals harbor somatically mutated cells with enhanced basal activity of the PI3K-AKT pathway.
To assess the impact of AKT3 (611223), PIK3R2 (603157), and PIK3CA mutations in individuals with megalencephaly on PI3K activity, Riviere et al. (2012) used immunostaining to compare PIP3 amounts in lymphoblastoid cell lines derived from 4 mutation carriers with megalencephaly to those in control and PTEN-mutant cells. Consistent with elevated PI3K activity, and similar to what is seen with PTEN (601728) loss, all 3 lines with PIK3R2 or PIK3CA mutations showed significantly more PIP3 staining than control cells, as well as greater localization of active phosphoinositide-dependent kinase-1 (PDPK1; 605213) to the cell membrane. Treatment with the PI3K inhibitor PI-103 resulted in less PIP3 in the PIK3R2 G373R (603157.0001) and PIK3CA glu453del (171834.0014) mutant lines, confirming that these results are PI3K-dependent. Riviere et al. (2012) found no evidence for increased PI3K activity in the AKT3-mutant line, consistent with a mutation affecting a downstream effector of PI3K. Protein blot analysis showed higher amounts of phosphorylated S6 protein and 4E-BP1 in all mutant cell lines compared to controls. Although PI-103 treatment reduced S6 phosphorylation in control and mutant lines, the latter showed relative resistance to PI3K inhibition, consistent with elevated signaling through the pathway. Riviere et al. (2012) concluded that the megalencephaly-associated mutations result in higher PI3K activity and PI3K-mTOR signaling.
To determine whether individuals with hemimegalencephaly and a mutation in PIK3CA (E545K; 171834.0003), AKT3 (E17K; 611223.0003), or MTOR (C1483Y) have aberrant mTOR signaling, Lee et al. (2012) immunostained brain sections of such cases with an antibody specific to the phosphorylated epitope of the S6 protein in a standard assay for the activation of mTOR signaling. Cells with the morphology of cytomegalic neurons were strongly labeled for phosphorylated S6 in the 3-prime-diaminobenzidine (DAB) staining of HME brains. In addition, Lee et al. (2012) coimmunostained for the neuronal marker MAP2, comparing samples with age-matched, similarly processed non-HME cortical hemisphere, and found a marked increase in the number of cells that were positive for phosphorylated S6 and greater intensity of staining for phosphorylated S6 in cytomegalic neurons of HME cases. Lee et al. (2012) concluded that these mutations are associated with increased mTOR signaling in affected brain regions.
Activating mutations in PIK3CA are frequently found in estrogen receptor (ER; see 133430)-positive breast cancer. Therapeutic PI3K-alpha inhibitors elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. Toska et al. (2017) investigated the chromatin-based mechanisms leading to the activation of ER upon PI3K-alpha inhibition and found that PI3K-alpha inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D (602113), a histone H3 lysine-4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3K-alpha inhibition enhances KMT2D activity. Toska et al. (2017) concluded that their findings uncovered a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
Yu et al. (2020) used a native mouse model of glioblastoma to develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. Yu et al. (2020) showed that tumors driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodeling of the synaptic constituency. Furthermore, they showed that secreted members of the glypican family are selectively expressed in these tumors, and that GPC3 (300037) drives gliomagenesis and hyperexcitability.
Studies using comparative genomic hybridization (CGH) revealed several regions of recurrent abnormal DNA sequence copy number (reviewed by Knuutila et al., 1998) that may encode genes involved in the genesis or progression of ovarian cancer (167000). One region at 3q26 found to be increased in copy number in approximately 40% of ovarian and other cancers contains the PIK3CA gene. This association between PIK3CA copy number and PI3-kinase activity made PIK3CA a candidate oncogene because a broad range of cancer-related functions had been associated with PI3-kinase-mediated signaling. Shayesteh et al. (1999) found that PIK3CA is frequently increased in copy number in ovarian cancers, and that the increased copy number is associated with increased PIK3CA transcription, p110-alpha protein expression, and PI3-kinase activity. Furthermore, treatment with a PI3-kinase inhibitor decreased proliferation and increased apoptosis. They concluded that PIK3CA is an oncogene that has an important role in ovarian cancer.
In comparative genomic hybridization studies, Ma et al. (2000) showed that 3q26.3 amplification was the most consistent chromosomal aberration in primary tissues of cervical carcinoma. They found a positive correlation between an increased copy number of PIK3CA (detected by competitive PCR) and 3q26.3 amplification in tumor tissues and in cervical cancer cell lines. In cervical cancer cell lines harboring amplified PIK3CA, the expression of the gene product was increased and was associated with high kinase activity. Other events suggested that increased expression of PIK3CA in cervical cancer may promote cell proliferation and reduce apoptosis.
Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC; 188470). They found frequent copy gains of RTK genes including EGFR (131550) and VEGFR1 (165070), and PIK3CA and PIK3CB (602925) in the P13K/Akt pathway. Copy number gain of PIK3CA was found in 18 of 47 ATCs (38%) and 15 of 63 FTCs (24%). RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.
Somatic Mutations in Cancer
Samuels et al. (2004) examined the sequences of 117 exons that encode the predicted kinase domains of 8 phosphatidylinositol-3 kinase genes and 8 PI3K-like genes in 35 colorectal cancers (114500). PIK3CA was the only gene with somatic mutations. Subsequent sequence analysis of all coding exons of PIK3CA in 199 additional colorectal cancers revealed mutations in a total of 74 tumors (32%). Samuels et al. (2004) also evaluated 76 premalignant colorectal tumors; only 2 mutations were found, both in very advanced tubulovillous adenomas greater than 5 cm in diameter. Thus, Samuels et al. (2004) concluded that PIK3CA mutations generally arise late in tumorigenesis, just before or coincident with invasion. Mutations in PIK3CA were also identified in 4 of 15 glioblastomas (27%), 3 of 12 gastric cancers (25%), 1 of 12 breast cancers (8%), and 1 of 24 lung cancers (4%). No mutations were observed in 11 pancreatic cancers or 12 medulloblastomas. In total, 92 mutations were observed, all of which were determined to be somatic in the cancers that could be assessed. Samuels et al. (2004) concluded that the sheer number of mutations observed in this gene strongly suggests that they are functionally important. Furthermore, most of the mutations were nonsynonymous and occurred in the PI3K helical and kinase domains, suggesting functional significance.
Pursuant to the report by Samuels et al. (2004) of a very high frequency of somatic mutations in PIK3CA in a large series of colorectal cancers, Campbell et al. (2004) investigated its relevance in other cancer types. They screened 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) analysis. Among 70 primary breast cancers, 28 (40%) harbored mutations in PIK3CA (see 171834.0001, 171834.0003, and 171834.0006), making it the most common mutation described up to that time in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, or grade or presence of tumor in lymph nodes. Among primary epithelial ovarian cancers, 11 of 167 (6.6%) contained somatic mutations (see 171834.0001, 171834.0003, and 171834.0005). Mutations were also identified among colorectal cancers (see 171834.0001-171834.0005). PIK3CA gene amplification (more than 7-fold) was common among all histologic subtypes and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers.
The phosphatidylinositol 3-prime-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the tumor suppressor gene PTEN. Broderick et al. (2004) identified 13 mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas, but not in ependymomas or low-grade astrocytomas. The consistency of hotspot mutations in PIK3CA across diverse tumor types suggested possible approaches to targeted therapy (e.g., development of agents acting as highly selective antagonists of the mutant allele products, sparing normal cells exhibiting wildtype PIK3CA activity).
Garcia-Rostan et al. (2005) analyzed 13 thyroid cancer cell lines, 80 well-differentiated follicular (WDFTC) and papillary (WDPTC) thyroid carcinomas, and 70 anaplastic thyroid carcinomas (ATC) for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 (23%) ATC cases, 2 (8%) WDFTC cases, and 1 (2%) WDPTC case. In 18 of 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component. Garcia-Rostan et al. (2005) concluded that mutant PIK3CA is likely to function as an oncogene in anaplastic thyroid carcinoma but less frequently in well-differentiated thyroid carcinomas.
Wu et al. (2005) found no PIK3CA gene mutations in 37 benign thyroid adenomas, 52 papillary thyroid cancers, 25 follicular thyroid cancers, 13 anaplastic thyroid cancers, 13 medullary thyroid cancers, and 7 thyroid tumor cell lines. They found a SNP in exon 20 in 2 cases, 1 in an adenoma and the other in a follicular thyroid carcinoma. With a copy number of 4 or more defined as amplification, they found PIK3CA gene amplification in 4 of 34 (12%) benign thyroid adenomas, 3 of 59 (5%) papillary thyroid cancer, 5 of 21 (24%) follicular thyroid cancer, 0 of 14 (0%) medullary thyroid cancer, and 5 of 7 (71%) thyroid tumor cell lines. The PIK3CA gene amplification and consequent AKT activation were confirmed by FISH and Western blotting studies using cell lines, respectively. The authors concluded that these data suggest that mutation of the PIK3CA gene is not common, but its amplification is relatively common and may be a novel mechanism in activating the P13K/AKT pathway in some thyroid tumors.
By specific analysis of exons 9 and 20 of the PIK3CA gene, Lee et al. (2005) detected somatic PIK3CA mutations in 26 (35.6%) of 73 hepatocellular carcinomas (114550), 25 (26.9%) of 93 breast carcinomas, 12 (6.5%) of 185 gastric carcinomas (137215), 1 (1.1%) of 88 acute leukemias, and 3 (1.3%) of 229 nonsmall cell lung cancers (211980). In all, 67 (10%) of the 668 samples harbored PIK3CA mutations. The most common mutations were E545A (171834.0008), H1047R (171834.0001), and 3204insA (171834.0007). Exons 9 and 20 encode the helical and kinase domains of the protein. Two cancers harbored 2 mutations each: an advanced gastric carcinoma and an invasive ductal breast carcinoma.
Bader et al. (2006) inoculated chick embryonic chorioallantoic membranes with embryonic fibroblasts transformed by the PIK3CA mutant proteins E542K, E545K (171834.0003), and H1047R and observed increased vascularization and the formation of neoplastic nodules. When the transformed embryonic fibroblasts were injected into the wing web of newly hatched chicks, hemangiomas or hemangiosarcomas developed at the site of injection. The H1047R mutant was the most potent carcinogen, causing the fastest growth rate and the highest incidence of tumors (80% compared to 50% induction with E542K or E545K). The tumors showed a high degree of angiogenesis and an activation of Akt (see 164730); a FRAP1 (601231) inhibitor, RAD001 (everolimus), blocked tumor growth induced by the H1047R mutant.
Karakas et al. (2006) provided a detailed review of the role of the PIK3CA oncogene in cancer.
By examining the mutation status of the PIK3CA gene in a panel of 60 human cancer cell lines, Whyte and Holbeck (2006) identified 8 heterozygous mutations in 7 cell lines (1 lung, 2 breast, 2 colon, and 2 ovarian cancer). Four mutations were in exon 9, 3 at codon 545 (E545K) and 1 at codon 549 (asp549 to asn, or D549N), and 4 mutations were in exon 20 at codon 1047 (H1047R). The D549N mutation was novel and occurred in a colon cancer cell line that also had an E545K mutation, suggesting that D549N may be a bystander mutation. PIK3CA mutant cell lines were more sensitive than PIK3CA wildtype cell lines to the estrogen receptor (ER, or ESR1; 133430) inhibitor tamoxifen, the AKT inhibitor triciribine, and other compounds. Whyte and Holbeck (2006) proposed that these insights into the role of mutant PIK3CA may enable identification of novel therapeutic targets for cancer.
By analyzing gene and protein expression data from 1,800 breast cancers, Loi et al. (2010) identified a PIK3CA mutation-associated gene signature derived from exon 20, which encodes the kinase domain. PIK3CA mutations were associated with low MTORC1 (see 601231) signaling and good prognosis with tamoxifen therapy in ER-positive/HER2 (ERBB2; 164870)-negative breast cancers, but these mutations were not associated with good prognosis in ER-negative/HER2-positive breast cancers.
Weigelt et al. (2011) tested the pharmacologic effects of the rapamycin analog everolimus, an allosteric mTORC1 inhibitor, and PP242, an active-site mTORC1/mTORC2 inhibitor, on a panel of 31 breast cancer (114480) cells. Cancer cells with activating PIK3CA mutations were selectively sensitive to both inhibitors, whereas those with loss-of-function PTEN (601728) mutations were resistant to treatment. In addition, a subset of cancer cells with HER2 amplification showed increased sensitivity to PP242, but not to everolimus, regardless of PIK3CA/PTEN mutation status. Both drugs exerted their effects by inducing G1 cell-cycle arrest. PP42 caused reduced downstream signal transduction of the mTOR pathway as evidenced by a decrease in AKT (164730) phosphorylation. The overall results indicated that PTEN and PIK3CA have distinct functional effects on the mTOR pathway. Weigelt et al. (2011) suggested that PIK3CA mutations in breast cancer may be a predictive marker to guide the selection of patients who would benefit from mTOR inhibitor therapy.
To characterize determinants of sensitivity to PI3K-alpha inhibitors such as alpelisib in cancer, Vasan et al. (2019) analyzed PIK3CA-mutant cancer genomes in approximately 70,000 patients from a publicly available cohort, 28,000 patients from an internal cohort, and several other cohorts. They observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types (most commonly uterine or colorectal cancer), and that most of these (95%) carried exactly 2 mutations. The double PIK3CA mutations were in cis and resulted in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. In the majority of cases, patients had a first hit involving a major hotspot mutation such as E542, E545, or H1047, and a second hit in a minor mutant site involving either E453, E726, or M1043. These recurrent mutational sites appeared to be specific to breast cancer. The biochemical mechanisms of dual mutations included increased disruption of p110-alpha binding to the inhibitory subunit p85-alpha, which relieves its catalytic inhibition, and increased p110-alpha membrane lipid binding. Vasan et al. (2019) concluded that double PIK3CA mutations predict increased sensitivity to PI3K-alpha inhibitors compared with single-hotspot mutations.
Vascular and Overgrowth Syndromes
Kurek et al. (2012) used massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from 6 patients with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918) and identified 3 different missense mutations in the PIK3CA gene (171834.0001, 171834.0009, and 171834.0010), with mutant allele frequencies ranging from 3 to 30% in affected tissue from multiple embryonic lineages. Noting that the 3 mutations had previously been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity, Kurek et al. (2012) concluded that CLOVE syndrome is caused by postzygotic activating mutations in PIK3CA, and hypothesized that the low rate of malignant transformation in patients with CLOVE syndrome is due to the low level of endogenous PIK3CA expression in most cells. The authors also found somatic mosaicism for the H1047R mutation (171834.0001) in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome.
Rios et al. (2013) identified 4 different mutations in the PIK3CA gene in affected tissue from 6 patients with macrodactyly (155500). One mutation (171834.0022) was novel.
Rodriguez-Laguna et al. (2018) screened 20 paired blood and tissue DNA samples from 9 patients of a cohort of 13 patients with a syndrome of capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial/generalized overgrowth (CLAPO; 613089) and identified 5 activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied. All mutations except 1 (F83S; 171834.0023) had previously been reported in a vascular/overgrowth disorder.
Hemifacial Myohyperplasia
By genotyping of affected muscle tissue from 5 patients with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaic mutations in the PIK3CA gene. Patients 1 and 5 had mosaicism for a glu545-to-lys mutation (E545K; 171834.0003), with mutation burdens of 15% and 14%, respectively. Patients 3 and 4 had mosaicism for a glu542-to-lys mutation (E542K; 171834.0009), with mutation burdens of 12% and 21%, respectively, and patient 2 had mosaicism for a his1047-to-arg mutation (H1047R; 171834.0013), with a mutation burden of 25%.
Cowden Syndrome 5
Among 91 individuals with Cowden syndrome who were negative for mutations in known disease-causing genes, Orloff et al. (2013) found that 8 carried mutations in the PIK3CA gene. None of these mutations was detected in 96 population controls, the Single Nucleotide Polymorphism database (dbSNP), or the available dataset of the 1000 Genomes Project. Functional assays demonstrated that these mutations resulted in upregulation of AKT1 phosphorylated at thr308 (P-AKT1-Thr308) and increased cellular PIP3.
Metastatic Cancer
Robinson et al. (2017) performed whole-exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 (191170), CDKN2A (600160), PTEN (601728), PIK3CA, and RB1 (614041). Putative pathogenic germline variants were present in 12.2% of cases, of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling.
Cerebral Cavernous Malformations 4
In 34 (39%) of 88 samples of cerebral cavernous malformations-4 (CCM4; 619538) from patients with sporadic occurrence of the disease, Peyre et al. (2021) identified 1 of 3 somatic missense mutations in the PIK3CA gene (H1047R, 171834.0001; H1047L, 171834.0002; and E542K, 171834.0009). The mutations were found by targeted DNA sequencing after studies in mice suggested that Pik3ca mutations can lead to CCM formation (see ANIMAL MODEL below). Four of the samples with PIK3CA mutations also had mutations in the CCM-related genes CCM1 (KRIT1; 604214), CCM2 (607929), and AKT1 (164730). The authors noted that cooccurrence of mutations is frequently seen in tumors. PIK3CA-mutant CCMs in humans and mice showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with activating mutations. Peyre et al. (2021) noted that the incidence of activating mutations in the PIK3CA gene in sporadic CCMs far exceeds that of mutations in CCM1, CCM2, or CCM3 (PDCD10; 609118), all of which cause familial disease. PIK3CA mutations were not observed in 11 samples of arteriovenous malformations.
To delineate the role of p110-alpha, a ubiquitously expressed phosphatidylinositide-3-hydroxykinase (PI3K) involved in tyrosine kinase and Ras (see 190020) signaling, Foukas et al. (2006) generated mice carrying a knockin mutation, D933A, that abrogates p110-alpha kinase activity. Homozygosity for this kinase-dead p110-alpha led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signaling via insulin-receptor substrate (IRS) proteins (e.g., 147545), key mediators of insulin, insulin-like growth factor-1 (IGF1; 147440), and leptin (164160) action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinemia, glucose intolerance, hyperphagia, and increased adiposity in mice heterozygous for the D933A mutation. This signaling function of p110-alpha derives from its highly selective recruitment and activation to IRS signaling complexes compared to p110-beta (602925), the other broadly expressed PI3K isoform, which did not contribute to IRS-associated PI3K activity. p110-alpha was the principal IRS-associated PI3K in cancer cell lines. Foukas et al. (2006) concluded that their findings demonstrated a critical role for p110-alpha in growth factor and metabolic signaling and also suggested an explanation for selective mutation or overexpression of p110-alpha in a variety of cancers.
Gupta et al. (2007) generated mice with mutations in the Ras-binding domain of Pi3kca. Cells from these mice had proliferative defects and selective disruption of signaling from growth factors to PI3K. In vivo, mutant mice displayed defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites. However, these mice were highly resistant to development of Ras oncogene-induced tumorigenesis. Gupta et al. (2007) concluded that interaction of Ras with PI3KCA is required in vivo for certain normal growth factor signaling and for Ras-driven tumor formation.
Soler et al. (2013) used syngeneic mouse cancer models to assess the importance of p110-alpha in the cancer stromal compartment. They found that treatment of a mouse melanoma cell line with an inhibitor of p110-alpha and p110-delta reduced Akt phosphorylation and Vegf production without affecting proliferation or survival. Tumor growth was blunted by the inhibitor, and tumors had increased numbers of small Cd31 (PECAM1; 173445)-positive blood vessels. Aberrant angiogenesis, reduced vessel function, and reduced Dll4 (605185) were also observed with p110-alpha/p110-delta inhibition in a lung cancer cell line mouse model. Soler et al. (2013) proposed that vessel size rather than vessel number is the key parameter in the antiangiogenic effect of p110-alpha inhibition.
Venot et al. (2018) developed a mouse model of CLOVES by creating mice that express a dominant-active PIK3CA transgene and ubiquitously express PIK3CA upon tamoxifen administration to induce Cre recombination. Three-week-old mice treated with a single dose of tamoxifen (40 mg/kg) began to die rapidly, with 50% mortality at day 9. Death occurred suddenly in most cases, with necropsy revealing intraabdominal and hepatic hemorrhages. Whole-body MRI showed scoliosis, vessel abnormalities, kidney cysts, and muscle hypertrophy. Histologic examination revealed liver steatosis with vessel disorganization, loss of spleen microarchitecture integrity, spontaneous hemorrhages, and fibrosis of the kidney with aberrant vessels. Venot et al. (2018) administered either BYL719 (alpelisib), a PIK3CA inhibitor, or placebo to mutant mice orally each day starting on the day of Cre induction. While all placebo-treated mutant mice died within 15 days, all BYL719-treated mutant mice were alive after 40 days and had an overtly normal appearance. Interruption of treatment after 40 days led to the rapid death of all mice. Administration of placebo or BYL719 7 days after Cre induction, when tissue abnormalities were already detected by MRI, resulted in improved survival in BYL719-treated mice. MRI after 12 days of treatment showed improvements in scoliosis, muscle hypertrophy, and vessel malformations. To more faithfully reproduce the lower mosaicism observed in patients, Venot et al. (2018) used a single dose of 4mg/kg of tamoxifen to induce Cre recombination. These mice survived for 2 months and then died with multiple phenotypic abnormalities including asymmetrical overgrowth of extremities, disseminated voluminous tumors, and visible subcutaneous vascular abnormalities. Histologic examination revealed the same lesions observed in human PIK3CA-related overgrowth. Treatment of these mice with BYL719 after lesions were clinically visible resulted in reduction and disappearance of all visible tumors within 2 weeks, with body weight loss. Notably, withdrawal of BYL719 led to recurrence of tumors, vascular malformations, and asymmetric extremity hypertrophy within 4 weeks.
Peyre et al. (2021) found that mutant mice selectively expressing the Pik3ca H1047R mutation in PGDS (602598)-expressing cells developed intraparenchymal CCM lesions, most of which were localized to the brainstem. Histologically, the lesions ranged from intraparenchymal vessel dilatations to capillary telangiectasia and the formation of young cavernous lesions. A subset of mice developed meningothelial proliferations. Peyre et al. (2021) noted that PGDS is expressed in pericytes surrounding intraparenchymal vessels, which is consistent with it being the most likely cell of origin.
Bayard et al. (2023) generated a mouse model with inducible muscle-specific expression of a constitutively overactivated form of PIK3CA.The mutant mice had progressive weight gain, muscle hypertrophy, and increased skeletal muscle strength compared to wildtype. Tissue histology showed diffuse muscle hypertrophy and adipose shrinkage. The mutant mice were also hypoglycemic and had low insulin and IGF1 levels with conserved insulin secretion. Western blotting and immunofluorescence showed AKT/mTOR activation in striated muscle. Treatment with alpelisib, a PIK3CA inhibitor, resulted in normalization of weight and skeletal muscle overgrowth and an increase in glucose, insulin, and IGF1 levels.
Colorectal Cancer
In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity.
Breast Cancer
In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20.
Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980).
CLOVE Syndrome
In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome.
Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome.
Seborrheic Keratosis
Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions.
Macrodactyly
Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis.
Cerebral Cavernous Malformations 4
In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation.
Variant Function
Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness.
Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity.
Breast Cancer
In 4 breast tumors (114480) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1340A-T transversion in exon 20 of the PIK3CA gene, resulting in a his1047-to-leu (H1047L) substitution.
CLOVE Syndrome
Lindhurst et al. (2012) 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 H1047L mutation in the PIK3CA gene in affected cells only, the p110-catalytic subunit of PI3K, only in affected cells, with a mutation burden determined to be from 8% to 39%. The same H1047L alteration was identified in 2 of 9 other individuals with the 'unclassified' syndrome, with mutation burdens ranging from 4% to 49%. The features of the syndrome were consistent with CLOVE syndrome (612918).
CLAPO Syndrome
In tissue from a lymphatic malformation (LM) of the tongue of a 7-year-old female patient (P13) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.3140A-T transversion (c.3140A-T, NM_006218.2) in the PIK3CA gene that resulted in a his1047-to-leu (H1047L) mutation in the kinase domain. The mutation was present at an allele frequency of 16% by deep sequencing, was present in 315 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 30 patients with vascular overgrowth disorders. Functional studies were not performed.
Cerebral Cavernous Malformations 4
In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 2 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047L mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation.
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution.
Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980).
Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions.
In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot.
In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5.
In 1 colorectal tumor (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1634A-G transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-gly (E545G) substitution.
Hafner et al. (2007) identified a heterozygous somatic E545G mutation in 9 (27%) of 33 epidermal nevus lesions (162900). The authors emphasized that these are benign lesions and noted that the same mutation had been observed in colorectal cancer. Two of the lesions had a concomitant somatic mutation in the FGFR3 gene (134934.0005).
In 1 epithelial ovarian tumor (167000) and 1 colorectal tumor (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1636C-A transversion in exon 9 of the PIK3CA gene, resulting in a gln546-to-lys (Q546K) substitution.
In 1 breast tumor (114480) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1636C-G transversion in exon 9 of the PIK3CA gene, resulting in a gln546-to-glu (Q546E) substitution.
In tissue samples from 13 (50%) of 26 hepatocellular carcinomas (114550) with PIK3CA mutations, Lee et al. (2005) identified a 1-bp insertion (3204insA) in exon 20 of the PIK3CA gene, resulting in a frameshift. One gastric cancer (137215) tumor also carried the mutation.
In tissue samples from 11 (42%) of 26 hepatocellular carcinoma (114550) with PIK3CA mutations, Lee et al. (2005) identified a 1634A-C transversion in exon 9 of the PIK3CA gene, resulting in a glu545-to-ala (E545A) substitution.
A complex germline mutation consisting of the E545A substitution and an insertion/deletion was found in an individual with Cowden syndrome (see 171834.0020).
CLOVE Syndrome
In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A transition in the PIK3CA gene, resulting in a glu542-to-lys (E542K) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 6 to 13%.
CLAPO Syndrome
In tissue from a lower lip capillary malformation (CM) from a 2-year-old female patient (P10) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.1624G-A transition (c.1624G-A, NM_006218.2) in the PIK3CA gene that resulted in a glu542-to-lys (E542K) mutation in the helical domain. The mutation was present at an allele frequency of 10% by deep sequencing, was present in 999 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 44 patients with vascular overgrowth disorders. Functional studies were not performed.
Cerebral Cavernous Malformations 4
In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 16 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic E542K mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation.
Hemifacial Myohyperplasia
In 2 patients (patients 3 and 4) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E542K mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on muscle biopsies from affected regions and found a mutation burden of 12% in patient 3 and 21% in patient 4.
CLOVE Syndrome
In a 15-year-old male and an unrelated 18-year-old female with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1258T-C transition in the PIK3CA gene, resulting in a cys420-to-arg (C420R) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 3 to 30%.
CLAPO Syndrome
In tissue from a lymphatic malformation (LM) of oral mucosa from a 11-year-old female patient (P6) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) detected a c.1258T-C transition in the PIK3CA gene that resulted in a cys420-to-arg (C420R) mutation in the C2 domain. The mutation was present at an allele frequency of 12% by deep sequencing, was present in 78 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 15 patients with vascular overgrowth disorders. Functional studies were not performed.
Riviere et al. (2012) conducted exome sequencing in an individual with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and his parents and performed an analysis of de novo mutations in this trio by including the raw variants that did not meet their initial hard-filtering criteria. Using this approach, they identified a 2740G-A transition in the PIK3CA gene, resulting in a gly914-to-arg (G914R) substitution. The mutation was supported by 20 of 177 reads (11%) in the exome sequencing data and was confirmed to be de novo and mosaic by Sanger sequencing and a custom restriction enzyme assay. This patient (LR09-006) had previously been reported by Mirzaa et al. (2012).
Riviere et al. (2012) performed standard variant calling in exomes from 7 individuals with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and identified a 1133G-A transition in the PIK3CA gene, resulting in a cys378-to-tyr (C378Y) substitution. The mutation was supported by 68 of 250 reads (27%) in 1 individual. This mutation showed variable levels of mosaicism depending on the tissue tested.
Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome
In 2 individuals with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified a de novo somatic mosaic 3139C-T transition in the PIK3CA gene, resulting in a his1047-to-tyr (H1047Y) substitution.
Hemifacial Myohyperplasia
In a patient (patient 2) with hemifacial myohyperplasia (HFMH; 606773) Bayard et al. (2023) identified mosaicism for the H1047R mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on a muscle biopsy from an affected region and found a mutation burden of 25%.
In a patient (LR11-153) with megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified a de novo somatic mosaic glu453-to-del (E453X) mutation in the PIK3CA gene. The same somatic mutation was also found in a patient (LR05-204) who was diagnosed with the overlapping megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; see 603387), although this patient did not have polydactyly.
In a 32-year-old man with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a G-to-A transition at nucleotide 353 in exon 2 of the PIK3CA gene, resulting in a glycine-to-aspartic acid substitution at codon 118 (G118D).
In a 54-year-old woman with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a G-to-A transition at nucleotide 403 in exon 2 of the PIK3CA gene, resulting in a glutamic acid-to-lysine substitution at codon 135 (E135K).
In a 44-year-old female with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a G-to-A transition at nucleotide 652 in exon 3 of the PIK3CA gene, resulting in a glutamic acid-to-lysine substitution at codon 218 (E218K).
In a 35-year-old female with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a G-to-A transition at nucleotide 1066 in exon 5 of the PIK3CA gene, resulting in a valine-to-isoleucine substitution at codon 356 (V356I).
In a 47-year-old male with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a G-to-A transition at nucleotide 1145 in exon 5 of the PIK3CA gene, resulting in an arginine-to-lysine substitution at codon 382 (R382K).
In a 71-year-old female with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) found heterozygosity for 2 mutations in exon 9 of the PIK3CA gene in cis: an A-to-C transversion at nucleotide 1634, resulting in a glutamine-to-alanine substitution at codon 545 (E545A); and a deletion of GT with insertion of a C (1658_1659delGTinsC) resulting in a serine-to-threonine substitution at codon 553, followed by a frameshift in termination codon 7 amino acids later (Ser553ThrfsTer7). This mutation was also identified in a 27-year-old female with Cowden syndrome.
In a 59-year-old male with Cowden syndrome (CWS5; 615108), Orloff et al. (2013) identified heterozygosity for a T-to-G transversion at nucleotide 1895 in exon 11 of the PIK3CA gene, resulting in a leucine-to-termination substitution at codon 632 (L632X).
Macrodactyly
In nerve tissue from a macrodactylous digit from a 5-year-old girl with macrodactyly (155500), Rios et al. (2013) detected a G-to-C transversion in exon 2 of the PIK3CA gene that resulted in an arginine-to-proline substitution at codon 115 (R115P). The mutation lies in a linker sequence between the adapter-binding and RAS-binding domains of the protein. The mutation was present at an allele frequency of 28% in the nerve exome and absent from the germline exome, and was not found in the Exome Variant Server database.
CLAPO Syndrome
Rodriguez-Laguna et al. (2018) detected the R115P mutation in capillary malformation (CM) tissue from 2 patients (P1 and P9) with CLAPO syndrome (613089). In P1 the mutation was present at an allele frequency of 12% and in P9 at an allele frequency of 16% in affected tissue. The mutation was present in 1 sample from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 6 patients with vascular overgrowth disorders. Functional studies were not performed.
In skin tissue with a capillary malformation (CM) from a 17-year-old female patient (P2) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.248T-C transition (c.248T-C, NM_006218.2) in the PIK3CA gene that resulted in a phe83-to-ser (F83S) substitution in the adapter-binding domain of the PIC3CA gene. This mutation was present at an allele frequency of 11% in affected tissue by deep sequencing, was present in 3 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had not been previously reported in patients with vascular overgrowth disorders. Functional studies were not performed.
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