PIK3CA mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors

Konopka, B; Janiec–Jankowska, Aneta; E, Kwiatkowska; Najmoła, Urszula; Bidziński, Mariusz; Olszewski, Włodzimierz; Goluda, Cyprian

doi:10.1016/j.humpath.2010.01.030

Cited by 52 publications

(49 citation statements)

References 33 publications

(78 reference statements)

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“…Mutations in PIK3CA , a gene within the same signalling pathway as PTEN , are also linked to type I endometrial carcinomas [27, 28]. In our data set, PIK3CA mutations occurred in 29% of the cases, which is in line with previous reports ranging between 16 and 52% [16, 17, 32, 33, 34], where the lowest frequencies can be explained by targeted sequencing (hot spot only). For PIK3CA mutations, a correlation was described with a poorer prognosis as a result of the correlation with higher tumour grade [16, 17].…”

Section: Discussionsupporting

confidence: 91%

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Next-Generation Sequencing in Gynaecological Tumours: The Prognostic and Predictive Value of the Most Common Mutations Found in Ovarian, Endometrial, and Cervical Tumours: Literature Review and the University Medical Centre Utrecht Next-Generation Sequencing Data

et al. 2017

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Objective: To investigate whether next-generation sequencing (NGS) in ovarian and endometrial tumours can discover mutations with a relevant prognostic or predictive value. Methods: After a literature search, selected studies were critically appraised using the Quality in Prognostic Studies tool. Data on mutation incidence and correlations with prognostic and predictive items were extracted from relevant studies and compared to our own cohort consisting of 28 patients analysed using NGS. Results: Eight out of 739 articles were found eligible, including different tumour types. Prevalence of mutations in the KRAS gene ranged between 5.34 and 58.8% in ovarian cancer. Two studies showed a significant correlation between KRAS mutations and an improved disease free- and overall survival. Clinical data were available for 17 of our patients, mostly cases of endometrial carcinomas. KRAS, PIK3CA, CTNNB1, and TP53 were the most frequently mutated genes in endometrial carcinomas, and PTEN and CTNNB1 correlated with a higher FIGO stage. Conclusion: In the ovary KRAS mutation is associated with type I ovarian tumours (low-grade serous, mucinous, endometrioid, and clear-cell) and may seem to have a more favourable prognosis. The prognostic value of TP53 is still controversial. In endometrial tumours, PTEN shows a positive correlation with better prognosis. PIK3CA may have a correlation with poorer prognosis. CTNNB1 mutations in endometrial carcinomas could predict a worse prognosis.

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Section: Discussionsupporting

confidence: 91%

“…In our samples this correlation was not found. Konopka et al [33] however describe a weak correlation between PIK3CA mutations and higher tumour grade. KRAS mutations occurred in 35% of our samples, which is slightly higher than previously reported rates of 10–31% [16, 17, 20, 27, 28].…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing in Gynaecological Tumours: The Prognostic and Predictive Value of the Most Common Mutations Found in Ovarian, Endometrial, and Cervical Tumours: Literature Review and the University Medical Centre Utrecht Next-Generation Sequencing Data

et al. 2017

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“…Our finding that amplification of the PIK3CA region and not PIK3CA mutations are associated with ER-a loss seems to be in line with this. Recent studies on other cancer types support that PI3K signaling activation may be related also to PIK3CA amplifications (50)(51)(52). Taken together, this suggests a potential for PI3K inhibitors for ER-a-negative tumors in particular.…”

Section: Discussionmentioning

confidence: 86%

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

Wik

Ræder

Krakstad

et al. 2013

Clinical Cancer Research

130

121

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Purpose: We hypothesized that estrogen receptor-a (ER-a) status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy.Experimental Design: Endometrial carcinoma samples in a primary investigation cohort (n ¼ 76) and three independent validation cohorts (n ¼ 155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.Results: ER-a immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-a negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-b signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-a and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-a-negative tumors. Low ER-a was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-a was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.Conclusion: Lack of ER-a in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-a's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-a-negative endometrial carcinomas.

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“…In line with this, we find higher PIK3CA copy number in pStathmin(S38)-high cases, potentially contributing to PI3K signaling activation in these tumors. Mutations in PIK3CA exons 1 to 20 and PIK3R1 are described for endometrial carcinomas (43)(44)(45). Several of the mutations in exon 9 and 20 have previously been associated with aggressive histopathologic features and suggested to be PI3K signaling activating mutations (44).…”

Section: Discussionmentioning

confidence: 99%

High Phospho-Stathmin(Serine38) Expression Identifies Aggressive Endometrial Cancer and Suggests an Association with PI3K Inhibition

Wik

Birkeland

Trovik

et al. 2013

Clinical Cancer Research

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Purpose: High Stathmin expression has recently been associated with clinical progress in endometrial cancers. Stathmin protein activity is modulated by phosphorylation, and the Serine38 site is one of four Stathmin phospho-sites. The presence and significance of pStathmin(S38) is largely unknown in human cancers, and we here examined the associations between this marker and tumor cell proliferation, clinicopathologic phenotype, and survival impact in endometrial cancer. A relationship with possible treatment targets was explored by integrated analysis of transcriptional alterations.Experimental Design: Primary endometrial cancers from two independent patient series (n ¼ 518/ n ¼ 286) were analyzed. Biomarkers were assessed by immunohistochemistry, FISH, flow cytometry, DNA oligonucleotide microarray, single-nucleotide polymorphism array, and Sanger sequencing, and related to clinicopathologic annotations and follow-up information.Results: High pStathmin(S38) level was associated with poor prognosis, independent of other features, and correlated to increased tumor cell proliferation as well as high Stathmin levels. On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (PI3K)/ mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases. High pStathmin(S38) was associated with several PI3K pathway alterations: amplification of the 3q26 region, increased PIK3CA copy number (FISH) and a PI3K activation score (all P < 0.05).Conclusions: High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer and not previously shown in human cancer. Our data support a rationale for further studies exploring effects of drugs inhibiting the PI3K signaling pathway in pStathmin(S38)-high endometrial cancer, including a potential value of pStathmin(S38) in predicting response to PI3K/mTOR/HSP90 inhibitors.

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PIK3CA mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors

Cited by 52 publications

References 33 publications

Next-Generation Sequencing in Gynaecological Tumours: The Prognostic and Predictive Value of the Most Common Mutations Found in Ovarian, Endometrial, and Cervical Tumours: Literature Review and the University Medical Centre Utrecht Next-Generation Sequencing Data

Next-Generation Sequencing in Gynaecological Tumours: The Prognostic and Predictive Value of the Most Common Mutations Found in Ovarian, Endometrial, and Cervical Tumours: Literature Review and the University Medical Centre Utrecht Next-Generation Sequencing Data

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

High Phospho-Stathmin(Serine38) Expression Identifies Aggressive Endometrial Cancer and Suggests an Association with PI3K Inhibition

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