PIK3CA Exon 20 Mutation is Independently Associated with a Poor Prognosis in Breast Cancer Patients

Lai, Yuen Liang; Mau, Bey Liing; Cheng, Wen; Chen, Han Ming; Chiu, Hsi Hsiung; Tzen, Chin Yuan

doi:10.1245/s10434-007-9751-7

Cited by 96 publications

(66 citation statements)

References 15 publications

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“…Although similar findings have been reported in high-grade ovarian carcinomas, 25 reports have been contradictory regarding the prognostic significance of the PIK3CA helical and kinase domain mutations in breast carcinomas. [26][27][28][29] However, it has been reported that chickens injected with exon 20 PIK3CA mutants developed larger tumors than those injected with exon 9 PIK3CA mutants. 30 The distinct associations of the different PIK3CA mutations with histologic type, grade, and depth of myometrial invasion in endometrial carcinomas is consistent with the idea that different categories of mutants, defined by their structural and functional domains, would increase PI3K function by diverse mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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The status of p53 and the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan-Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P ¼ 0.000). Although alterations in the PI3K-AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P ¼ 0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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“…Studies have demonstrated a better overall survival (OS) and disease free survival (DFS) in breast cancer patients with PI3KCA mutations when compared with that of breast cancer patients without these mutations (Maruyama, 2007;Stemke-Hale et al, 2008;Kalinsky et al, 2009;Dupont, 2011). However, others showed that PI3KCA mutations in breast cancer patients are associated with poor clinical outcome (Li, 2006;Barbareschi et al, 2007;Lai et al, 2008). Our aim of this study is to identify mutational status of the two hotspot regions of PIK3CA (exons 9 and 20) in breast cancer.…”

Section: Phosphatidylinositol 3-kinase (Pi3kca) Oncogene Mutation Anamentioning

confidence: 99%

Phosphatidylinositol 3-kinase (PI3KCA) Oncogene Mutation Analysis and Gene Expression Profiling in Primary Breast Cancer Patients

Kandula¹,

Chennaboina²,

Ys³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…Since then, more than 1,500 PIK3CA mutations in diverse tumor types have been discovered (6). The most common mutant is His1047Arg (6), and mutations at this residue in breast and uterine cancers are associated with clinical prognosis (7)(8)(9). Biochemical assays have demonstrated that the His1047Arg mutant has a 2-fold increase in lipid kinase activity (10), that its activity increases further upon phosphopeptide binding (10), and that the activity is independent of Ras binding but dependent on p85 binding (11).…”

mentioning

confidence: 99%

A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane

Mandelker

Gabelli²,

Schmidt‐Kittler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

267

383

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Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110␣, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3K␣), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110␣ in complex with two interacting domains of its regulatory partner (p85␣), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85␣ is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110␣. Moreover, we found that Arg-1047 points toward the cell membrane, perpendicular to the orientation of His-1047 in the WT enzyme. Surprisingly, two loops of the kinase domain that contact the cell membrane shift conformation in the oncogenic mutant. Biochemical assays revealed that the enzymatic activity of the p110␣ His1047Arg mutant is differentially regulated by lipid membrane composition. These structural and biochemical data suggest a previously undescribed mechanism for mutational activation of a kinase that involves perturbation of its interaction with the cellular membrane.

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PIK3CA Exon 20 Mutation is Independently Associated with a Poor Prognosis in Breast Cancer Patients

Cited by 96 publications

References 15 publications

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Phosphatidylinositol 3-kinase (PI3KCA) Oncogene Mutation Analysis and Gene Expression Profiling in Primary Breast Cancer Patients

A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane

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