Frequent Activating Mutations of PIK3CA in Ovarian Clear Cell Carcinoma

Kuo, Kuan-Ting; Mao, Tsui Lien; Jones, Siân; Veras, Emanuela; Ayhan, Ayşe; Wang, Tian Li; Glas, Ruth; Slamon, Dennis J.; Velculescu, Victor E.; Kuman, Robert J.; Shih, Ie Ming

doi:10.2353/ajpath.2009.081000

Cited by 410 publications

(329 citation statements)

References 34 publications

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“…3,16 Tumor components from formalin-fixed and paraffin-embedded tissue blocks were manually dissected from 10-mm sections. Genomic DNA of tumor tissue was extracted using the QIAmp DNA FFPE tissue kit (Qiagen, CA).…”

Section: Dna Extraction and Mutation Analysismentioning

confidence: 99%

“…The primer sets used for PIK3CA were listed as follows: 5 0 -TCAGCAGTTACTATTCTGTGACTGG-3 0 (forward primer) and 5 0 -GTAAAACGACGGCCAG TTGCTGAGATCAGCCAAATTCA-3 0 (reverse primer) for exon 9, as well as 5 0 -GTAAAACGACGGCCAG TGACATTTGAGCAAAGACCTGAAG-3 0 (forward primer) and 5 0 -TGGATTGTGCAATTCCTATGC-3 0 (reverse primer) for exon 20. 3 Two primer sets were used for TERT promoter. 16 Primer set no.…”

Section: Dna Extraction and Mutation Analysismentioning

confidence: 99%

“…1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy. [2][3][4] Primary endometrial clear cell carcinoma (which has similar histologic characteristics to ovarian clear cell carcinoma) is a rare histologic type that accounts for less than 3% of all endometrial carcinomas. 5,6 Interobserver reproducibility of endometrial clear cell carcinoma was poor, 7,8 and a panel of hepatocyte nuclear factor-1b (HNF-1b) and estrogen receptor (ER) immunohistochemistry was suggested for differentiation of endometrial clear cell carcinoma from endometrioid and serous carcinoma.…”

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Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (Po0.001), preserved ARID1A immunoreactivity (P ¼ 0.017) and infrequent PIK3CA mutation (P ¼ 0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age 445 (P ¼ 0.045) and preserved ARID1A expression (P ¼ 0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P ¼ 0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P ¼ 0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy. Modern Pathology (2015) 28, 303-311; doi:10.1038/modpathol.2014 published online 1 August 2014 Ovarian clear cell carcinoma represents 5-25% of all epithelial ovarian carcinomas with geographic variation. 1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy.

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Section: Dna Extraction and Mutation Analysismentioning

confidence: 99%

Section: Dna Extraction and Mutation Analysismentioning

confidence: 99%

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confidence: 99%

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Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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“…In OCCC, like numerous other cancers (43,44), somatic mutations in the PIK3CA gene have been common and highly frequent (24,45,46). The PIK3CA gene, encoding the catalytic subunit p110α of PI3K, is located on chromosome 3q26.3 and mutation and/or amplification of this locus has been shown to increase PI3K activity (43,47).…”

Section: Expression Of Several Proteins Related To Glycogen Metabolismentioning

confidence: 99%

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

et al. 2012

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Abstract. Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1α, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3β via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs.

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“…Le carcinome à cellules claires (CCC) représente 10 à 12 % des cas et correspond à l'une des formes les plus agressives en raison de sa faible chimiosensibilité [2,3]. Peu étudié au niveau moléculaire, il présente moins d'insconcernaient des mutations de gènes impliqués dans l'oncogenèse en géné-ral (CTNNB1 qui code la -caténine, KRAS, PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit ] et TP53) et l'amplification de la région chromosomique 20q13.2 [5,6]. Deux études récentes basées sur le séquençage du génome tumoral décri-vent des mutations somatiques du gène ARID1A (AT-rich interactive domaincontaining protein 1A), qui jouerait ainsi un rôle de gène suppresseur de tumeurs (GST) [7,8].…”

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