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PubMed2006

Clinical significance of immunocytochemistry for PIK3CA as a carcinogenesis-related marker on liquid-based cytology in cervical intraepithelial neoplasia.

The catalytic subunit alpha of phosphatidylinositol 3-kinase (PIK3CA) has been expected to play a role as an important oncogene in uterine cervical carcinoma, whose expression in non-invasive lesions has received considerable attention. We investigated the potential of PIK3CA as a carcinogenesis-related marker for early intraepithelial lesion of the uterine cervix in cytology samples. Seventy-four cases with abnormal cytology suggesting the existence of cervical intraepithelial neoplasia (CIN) lesions, whose findings were histologically confirmed, were selected; they consisted of 20 CIN1, 21 CIN2, and 33 CIN3, respectively. In addition, 17 normal cases, whose cervical cytology revealed no abnormality over three occasions, were selected. Liquid-based cytology specimens were applied for human papillomavirus (HPV) DNA typing and immunocytochemistry using three different antibodies for p16(INK4a), Ki-67 and PIK3CA, respectively. The fraction of immunopositive cells on the slides was calculated and expressed as mean numbers. Receiver operating characteristic (ROC) plots were generated to determine the diagnostic accuracy of each immunocytochemistry test. The mean number of immunopositive cells in the CIN3 group was significantly higher than other groups for all three antibodies. Among all groups, PIK3CA showed a superior specificity to distinguish CIN3 from other groups. Comparison of three markers by ROC curves also revealed that PIK3CA provided the best method for distinguishing CIN3. Thus, expression of PIK3CA was observed in liquid-based cytology in CIN lesions, which suggested its diagnostic significance in addition to the use of routine cervical cancer smear and the HPV screening program.

Biomarkers, Tumor↗
PubMed2005

PIK3CA mutations in breast cancer are associated with poor outcome.

The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is considered to play an important role in tumorigenesis. Frequent somatic mutations in the PI3K subunit p110alpha (PIK3CA) occur in a variety of cancer types. We screened 250 primary human breast tumors for mutations in PIK3CA in order to determine associations with pathological features and with patient outcome. The frequency of PIK3CA mutations in the C2, helical and kinase domains was 35% (88/250). Mutations were associated with larger tumor size (p = 0.004) and positive estrogen receptor status (p = 0.008). Patients with PIK3CA mutations showed significantly worse survival (p = 0.004), particularly those with positive estrogen receptor expression or non-amplified erbB2 (both p = 0.002). PIK3CA mutation was an independent factor for worse survival in breast cancer patients with non-amplified erbB2 (RR = 2.6, 95%CI [1.2-5.5], p = 0.016).

Adolescent↗
PubMed2005

Comparison of phosphatidylinositol-3-kinase signalling within a panel of human colorectal cancer cell lines with mutant or wild-type PIK3CA.

Recent studies have identified conserved missense mutations in PIK3CA, the gene encoding the catalytic phosphatidylinositol-3-kinase subunit p110alpha, in a variety of human cancers. Further investigation demonstrated that PIK3CA mutations lead to increased basal phosphatidylinositol-3-kinase activity, promoting cell growth and invasion [Samuels, Y., Diaz, L.A., Jr., Schmidt-Kittler, O., Cummins, J.M., Delong, L., Cheong, I., Rago, C., Huso, D.L., Lengauer, C., Kinzler, K.W., Vogelstein, B. and Velculescu, V.E. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561-573]. A panel of commonly used colorectal cancer cell lines was screened for these PIK3CA mutations. Constitutive and IGF-1-stimulated phosphatidylinositol-3-kinase activity, signal response and duration were assessed. In the assays used no differences distinguished cells carrying PIK3CA mutations indicating that these mutations did not significantly alter growth factor stimulated or steady state phosphatidylinositol-3-kinase activity in normal cell culture conditions.

Biomarkers, Tumor↗
PubMed2006

Mutations of PIK3CA are rare in cutaneous melanoma.

Recent studies have shown that the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinases, is mutated in human cancers. To determine whether PIK3CA is altered in cutaneous melanoma, we screened a series of 101 melanoma metastases. We identified PIK3CA missense mutations in three metastases (3%). Interestingly, these mutations were observed only in tumours that were negative for NRAS mutations. Using immunohistochemistry, we also analysed our metastases for the expression of phosphorylated Akt. These analyses revealed a moderate to strong phosphorylated Akt expression in 78% (21 of 27) of metastases with NRAS mutations and in 73% (54 of 74) of metastases without NRAS mutations. Interestingly, the three metastases with mutations in PIK3CA all exhibited a strong expression of phosphorylated Akt. Taken together, our results show that PIK3CA is mutated in a minority of melanomas and suggest that mutations in this gene may represent an alternative mechanism of Akt activation in cutaneous melanoma.

Class I Phosphatidylinositol 3-Kinases↗
PubMed2004

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.

The phosphatidylinositol 3'-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3'-kinase catalytic subunits, were identified in a significant fraction (25-30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major "hot spots" located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.

Astrocytoma↗
PubMed2005

Frequent mutation of the PIK3CA gene in ovarian and breast cancers.

PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, resulting in increased cell proliferation, survival, and motility, is believed to play an oncogenic role in many cancer types. The PIK3CA gene encodes the p110alpha catalytic subunit of PI3K, and is amplified in some ovarian cancers, whereas the AKT2 gene is amplified in some ovarian, breast, and pancreatic cancers. Recently, in a mutational screen of eight PI3K genes and eight PI3K-like genes, PIK3CA was found to be the only gene affected by somatic mutations, which were observed frequently in gastrointestinal and brain cancers. Here, we test whether PIK3CA is subject to mutation in ovarian and breast cancers. EXPERIMENTAL DESIGN: Exons 9 and 20, encoding the highly conserved helical and kinase domains of PIK3CA, were subjected to sequence analysis in 198 advanced stage epithelial ovarian carcinomas and 72 invasive breast carcinomas (48 of ductal histology and 24 of lobular histology). RESULTS: Somatic missense mutations were observed in 24 of 198 (12%) ovarian carcinomas, and in 13 of 72 (18%) breast carcinomas. CONCLUSIONS: These data indicate that mutations of PIK3CA play an oncogenic role in substantial fractions of ovarian and breast carcinomas, and in consideration of mutation of other components of the PI3K-AKT pathway in both tumor types, confirm the major oncogenic role of this pathway in ovarian and breast carcinomas.

Base Sequence↗
PubMed2024

Identification of breast cancer-associated PIK3CA H1047R mutation in blood circulation using an asymmetric PCR assay.

PURPOSE: To establish a highly sensitive and specific approach for the detection of circulating PIK3CA H1047R mutation in breast cancer (BC) patients and to investigate the association between the prevalence of PIK3CA H1047R mutation and clinical presentations. METHODS: A proper blocker was designed in an allele-specific manner and optimized for PCR-based identification of the PIK3CA H1047R mutation. The established technique was validated in cell-free DNA samples from 196 recruited BC patients. RESULTS: The allele-specific PCR assay with a properly designed blocker was able to detect the H1047R mutant variant with 0.01%. By applying the newly established assay, 62 cases (31.6% of the total recruited cases) were found to carry a blood-circulating H1047R mutant. Wherein, the detected mutant rates increased with disease stages from 2/18 (11.1%) of stage I to 17/71 (23.9%) of stage II, 20/53 (37.7%) of stage III, and 23/31 (42.6%) of stage IV (p = 0.025), respectively. Higher frequencies of H1047R mutation were associated with late-stage (p = 0.033) or recurrence (p = 0.045) or metastatic patients (p = 0.049) as well as radiation-treated human epidermal growth factor receptor 2 (HER2) positive BC (p = 0.004). PIK3CA mutant carriers were frequently observed in patients under the age of 50 who had liver-metastasized or brain metastases or lymph node-invaded (p < 0.05). CONCLUSION: A novel allele-specific PCR assay with high sensitivity was established successfully for the detection of the PIK3CA H1047R mutation in clinical practice.

Humans↗
PubMed2006

Mutational hotspot in exon 20 of PIK3CA in breast cancer among Singapore Chinese.

The recent identification of somatic mutations in the catalytic region of PIK3 (PIK3CA) in breast cancer and demonstration of their oncogenic function has implicated PIK3CA in mammary carcinogenesis. To investigate possible ethnic differences in patterns of PIK3CA mutations in Singaporean Chinese breast cancer and to characterize these in a panel of cell lines, we sequenced exons 9 and 20 in 80 primary tumors, 19 breast cancer cell lines and 7 normal human mammary epithelial cells (HMECs). Searching for novel hotspots of mutation, we sequenced additional exons (1, 2, 6, 7, 14 and 18) in 20 primary tumors and 6 breast cancer cell lines. We detected 33 point mutations in 31 of 80 (39%) breast cancers, and 11 mutations in 10 of 19 (53%) breast cancer cell lines. No mutations were detected in normal breast tissue adjacent to the tumor, or in the 6 normal HMECs. The exon 20 A3140G (H1047R) substitution was identified most frequently (22/31, 71%) and showed a significant association with patient age (p = 0.043) and stage of the disease (p = 0.025), but not with ER/PR status or histological grade of the tumor. The incidence of point mutations in PIK3CA, the A3140G substitution in particular, in Singapore breast cancers are among the most frequent reported to date for any gene in breast cancer. The results suggest that mutation of PIK3CA might contribute to development of early stage breast cancer and could provide a potent target for early diagnosis and therapy.

Asian People↗
PubMed2026

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability.

PIK3CA, which encodes the p110&#x3b1; catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3K&#x3b1; complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

PI3K signaling↗
PubMed2005

PIK3CA mutations in advanced ovarian carcinomas.

PIK3CA belongs to the phosphatidylinositol 3-kinases (PI3Ks) family, which play an important role in proliferation, adherence, transformation and cell survival through the PI3K/AKT signaling pathway. Somatic activating mutations of this gene have recently been detected in several types of cancers. In the present study, 109 advanced ovarian carcinomas were analyzed for PIK3CA mutations in exon 9 and exon 20 by direct sequencing. Activating missense mutations were observed in 4 of the 109 tumors in addition to one variant leading no change of the PIK3CA protein. Two of the cases with mutations were mucinous and clear cell tumors, suggesting that PIK3CA mutations are more common in these rare histological types.

Adenocarcinoma, Clear Cell↗
PubMed2006

Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation.

Uterine cervical carcinogenesis is probably dependent on cellular genetic damage in addition to the integration of high-risk HPV DNA in the epithelial cell genome. Gain of chromosome 3q24-29 is commonly observed in cervical neoplasia. The putative oncogene PIK3CA located in this region encodes a phosphatidylinositol 3-kinase (PI3K). In a process reversed by PTEN, PI3K generates inositol phospholipids that trigger AKT phosphorylation, which in turn effects tumor driving signals. We studied 46 specimens of formalin-fixed, paraffin-embedded cervical neoplastic tissue. The activation state of the PI3K-AKT pathway was assessed immunohistochemically using an antibody with specificity towards serine 473-phosphorylated AKT. AKT phosphorylation was found in 39 out of 46 examined specimens. To examine the possible molecular basis for this activation, we searched for PIK3CA amplification using quantitative real-time polymerase chain reaction. PIK3CA gene copy number was estimated to be 3 or more in 28 out of 40 successfully examined cases. Further, a PTEN mutation analysis of all 9 PTEN exons was carried out, but except for 1 metastasis with an exon 9 V369I heterozygosity, all cases showed normal PTEN sequence. Immunohistochemical staining for PTEN was strong in all lesions. In conclusion, an increased activation state of AKT kinase appears to be present in cervical carcinogenesis, and may be accounted for by PIK3CA amplification, whereas PTEN mutation seems to be of little importance.

Carcinoma, Squamous Cell↗
PubMed2002

Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma.

PIK3CA, encoding the catalytic subunit p110alpha of phosphatidylinositol 3-kinase (PI3K), is activated in malignant diseases. However, the role of the PIK3CA gene aberrations for tumourigenesis of head and neck squamous cell carcinoma (HNSCC) is to date unclear. The present study was designed to determine the genomic aberration of PIK3CA in invasive HNSCC and dysplastic precursor lesions by fluorescence in situ hybridization (FISH) with a YAC probe, containing the PIK3CA gene, on isolated interphase nuclei from histomorphologically well-defined regions of formalin-fixed tissue sections and to compare these data with protein and mRNA expression of p110alpha. The mRNA and protein levels of p110alpha were assessed, respectively, by in situ hybridization and immunohistochemistry on consecutive tissue sections. Copy number gains at 3q26 were observed in one of six low-to-moderate dysplasias (17%) and in seven of nine high-grade dysplasias (78%), as well as in 11 carcinomas (100%). In addition, one of seven high-grade dysplasias (14%) and 6 of 11 carcinomas (55%) had amplifications of 3q26. The majority of cases with copy number gain in more than 50% of the cells and/or amplification in more than 10% of cells showed increased p110alpha mRNA and protein expression, whereas only two cases (18%) (one high-grade dysplasia and one carcinoma) with no gain or low-level gain displayed increased p110alpha protein expression. These data suggest that 3q26 copy number gain and amplification represent early genomic aberrations in HNSCC carcinogenesis. In addition, p110alpha mRNA and protein expression in HNSCC may be regulated by these genomic aberrations as well as by epigenetic events.

Adult↗
PubMed2006

Amplification of CCND1, EMS1, PIK3CA, and ERBB oncogenes in ethmoid sinus adenocarcinomas.

OBJECTIVE: Assess the amplification of CCND1, EMS1, PIK3CA, ERBB1, and ERBB2 oncogenes in ethmoid sinus adenocarcinomas. STUDY DESIGN AND SETTING: Tissue samples from 13 primary ethmoid adenocarcinomas and 2 recurrences were studied at Hospital Central de Asturias, Oviedo, Spain, between July 1998 and February 2002. A semiquantitative evaluation of CCND1, EMS1, PIK3CA, ERBB1, and ERBB2 amplification was performed by multiplex polymerase chain reaction. RESULTS: Three (23%) cases presented CCND1 amplification, one of them with a concurrent PIK3CA amplification. EMS1 was amplified in the 2 studied recurrences. ERBB1 was amplified in 1 case (8%), whereas none presented ERBB2 amplification. Oncogenic amplifications were only detected in advanced (stage III) tumors; however, no prognostic value could be shown for them. CONCLUSIONS: CCND1, EMS1, PIK3CA, and ERBB1 amplifications are uncommon and appear to be late events in the development of ethmoid sinus adenocarcinoma. SIGNIFICANCE: New information on the carcinogenesis of this infrequent sinonasal tumor is presented.

Adenocarcinoma↗
PubMed2002

p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas.

Interactions between the p53 and PI3K/AKT pathways play a significant role in the determination of cell death/survival. In benign cells these pathways are interrelated through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis. PTEN exerts its effects by decreasing the phosphorylated AKT fraction, thereby diminishing prosurvival activities. However, the link between these pathways in cancer is not known. In this study, PIK3CA, encoding the p110alpha catalytic subunit of PI3K, is identified as an oncogene involved in upper aerodigestive tract (UADT) carcinomas. Simultaneous abnormalities in both pathways are rare in primary tumors, suggesting that amplification of PIK3CA and mutation of p53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect of p53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTEN activity, as PTEN is not expressed in the primary tumors. Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells. Thus, p53 regulates cell survival by inhibiting the PI3K/AKT prosurvival signal independent of PTEN in epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells.

Apoptosis↗
PubMed2026

High tumor mutational burden and PIK3CA mutations correlate with poor Merkel cell carcinoma-specific survival.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04-25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10-3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.

Humans↗
PubMed2014

Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow.

BACKGROUND: Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. METHODS: We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. RESULTS: Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. CONCLUSIONS: Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.

Bone Marrow↗
PubMed2004

The PIK3CA gene is mutated with high frequency in human breast cancers.

The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation. It has recently been reported that somatic mutations within the PI3K subunit p110alpha (PIK3CA) are present in human colorectal and other cancers. Here we show that thirteen of fifty-three breast cancers (25%) contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain. These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis.

Biomarkers, Tumor↗
PubMed2005

Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line.

OBJECTIVE: The aim of this study was to understand the role of PIK3CA and PTEN on the resistance of human ovarian cancer cells to cisplatin-induced apoptosis. METHODS: Human ovarian cancer cell OVCAR-3 and cisplatin-resistant subclone OVCAR-3/CDDP cells were used for these studies. The expressions of apoptosis regulating proteins and PI3K/Akt signaling proteins were systematically examined. RESULTS: OVCAR-3/CDDP cells were 4.8-fold more resistant to cisplatin compared to OVCAR-3 cells following 72 h exposure to this drug. This resistance was paralleled with reduced susceptibility to cisplatin-induced apoptosis. Apoptotic proteins were differentially expressed in OVCAR-3/CDDP cells, resulting in the inhibition of Bax translocalization. Cisplatin inhibited Akt phosphorylation and activation in OVCAR-3 cells but not in OVCAR-3/CDDP cells. The specific PI3K inhibitors LY294002 and wortmannin sensitized OVCAR-3/CDDP cells to cisplatin-induced apoptosis and decreased cell viability. A low level of PTEN expression was strongly associated with amplified PIK3CA and PI3K/Akt activities in OVCAR-3/CDDP cells. Small interfering RNA knockdown of PTEN and the expression of active p110alpha resulted in a blockade of apoptosis by cisplatin in OVCAR-3 cells. CONCLUSIONS: These results collectively indicate that the development of resistance in OVCAR-3 cells was derived by increased PIK3CA transcription and reduction of PTEN expression. These alterations conferred cisplatin resistance to cisplatin through the activation of PI3K/Akt and the inhibition of Bax translocation.

Apoptosis↗