PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters

Catasús, Lluis; Gallardo, Alberto; Cuatrecasas, Míriam; Prat, Jaime

doi:10.1038/modpathol.3800992

Cited by 114 publications

(95 citation statements)

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“…We have investigated recently the PIK3CA status in a large series of endometrioid adenocarcinomas and compared the results with the clinical and pathologic parameters associated with prognosis. 16 In our series, the PIK3CA mutations occurred in 29% of endometrioid adenocarcinomas, all with myometrial invasion. We also found that histologic type, grade, and depth of myometrial invasion varied significantly depending on the location of PIK3CA mutations, either in exon 9 or exon 20.…”

mentioning

confidence: 49%

“…16 Of the 30 highgrade carcinomas included in this study, the PIK3CA mutations were found in 21% (3/14) nonendometrioid adenocarcinomas and in 44% (7/16) mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. All the PIK3CA mutations found in non-endometrioid adenocarcinomas and in mixed carcinomas occurred in exon 20 ( Figure 1).…”

Section: Pik3ca Mutations and Gene Expressionmentioning

confidence: 80%

“…Most of the cases (102 endometrioid adenocarcinomas) have been the subject of an earlier investigation. 16 In this study, 30 high-grade carcinomas (14 non-endometrioid adenocarcinomas and 16 mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas) were included. Genomic DNA from tumors and the corresponding non-tumor tissues was extracted using standard methods from frozen biopsies.…”

Section: Tissue Samples and Dna Isolationmentioning

confidence: 99%

“…We also found that histologic type, grade, and depth of myometrial invasion varied significantly depending on the location of PIK3CA mutations, either in exon 9 or exon 20. 16 PTEN is a tumor-suppressor gene located in chromosome 10q23.3, a genomic region undergoing loss of heterozygosity in a wide variety of human cancers. PTEN encodes a phosphatase that antagonizes the PI3K-AKT pathway by dephosphorylating PIP3, a product of PI3K.…”

mentioning

confidence: 99%

“…In an earlier investigation, we found somatic PTEN mutations in 51-54% of endometrial carcinomas and they were far more frequent in endometrioid adenocarcinomas than in non-endometrioid adenocarcinomas. 5,16 P53 mutations are the most characteristic genetic alterations of non-endometrioid adenocarcinomas. P53 is a tumor-suppressor gene located in 17p13.1 that encodes p53 protein, a transcription factor that induces the expression of genes necessary for cell cycle arrest and apoptosis in response to DNA damage.…”

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confidence: 99%

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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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confidence: 49%

Section: Pik3ca Mutations and Gene Expressionmentioning

confidence: 80%

Section: Tissue Samples and Dna Isolationmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

et al. 2009

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Association of epidermal growth factor receptor mutations with human papillomavirus 16/18 E6 oncoprotein expression in non–small cell lung cancer

Tung

Cheng³

et al. 2013

Cancer

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BACKGROUND: Lung cancers in women, in nonsmokers, and in patients with adenocarcinoma from Asia have more prevalent mutations in the epidermal growth factor receptor (EGFR) gene than their counterparts. However, the etiology of EGFR mutations in this population remains unclear. The authors hypothesized that the human papillomavirus (HPV) type 16=18 (HPV16=18) E6 oncoprotein may contribute to EGFR mutations in Taiwanese patients with lung cancer. METHODS: One hundred fifty-one tumors from patients with lung cancer were enrolled to determine HPV16=18 E6 and EGFR mutations using immunohistochemistry and direct sequencing, respectively. Levels of 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-oxo-dG) in lung tumors and cells were evaluated using immunohistochemistry and liquid chromatography-mass spectrometry=mass spectrometry. An supF mutagenesis assay was used to determine H 2 O 2 -induced mutation rates of lung cancer cells with or without E6 expression. RESULTS: Patients with E6-positive tumors had a greater frequency of EGFR mutations than those with E6-negative tumors (41% vs 20%; P 5.006). Levels of 8-oxo-dG were correlated with EGFR mutations (36% vs 16%; P 5.012). Two stable clones of E6-overexpressing H157 and CL-3 cells were established for the supF mutagenesis assay. The data indicated that the cells with high E6 overexpression had higher H 2 O 2 -induced SupF gene mutation rates compared with the cells that expressed lower levels of E6 and compared with vector control cells. CONCLUSIONS: HPV16=18 E6 may contribute in part to EGFR mutations in lung cancer, at least in the Taiwanese population. Cancer 2013;119:3367-76. V C 2013 American Cancer Society.KEYWORDS: epidermal growth factor receptor; mutation; 8-oxo-7; 8-dihydro-2& prime;-deoxyguanosine; human papillomavirus; lung cancer. INTRODUCTIONLung cancer is the leading cause of cancer death and predominantly is induced by tobacco smoke. However, approximately 25% of all lung cancer worldwide is not attributed to smoking. 1,2 In addition, nonsmokers with lung cancer are identified more often Asian women than among Caucasian women. 3,4 Lung cancer in nonsmokers has recently been recognized as a disease entity distinct from tobacco smoke-associated lung cancer. 5,6 The activation of epidermal growth factor receptor (EGFR) by its gene mutations, including exon 19 in-frame deletions and exon 21 L858R substitution, are currently recognized as the most potent biologic predictors of EGFR tyrosine kinase inhibitor (TKI) sensitivity. 7 These mutations are observed in approximately 40% to 60% of lung cancers in neversmokers, compared with approximately 10% to 20% of tobacco smoke-related lung cancers. 8,9 Therefore, an exploration of the etiologic factor(s) in EGFR mutations may be useful in the prevention of lung cancer in nonsmokers, particularly among women.A high frequency of EGFR mutations are common in nonsmoking women with lung adenocarcinoma in Asian populations, including Taiwanese. 3,4 Nonsmokers with lung cancer more prevalently present with an adenocarci...

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Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

García-Sanz

Triviño

Mota

et al. 2017

Intl Journal of Cancer

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In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low-grade, non-ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE-positive endometrioid endometrial carcinomas (EECs). We performed exome-sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling-related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA-repair-related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co-occurrence (RAD50-KMT2D and RAD50-SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.

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PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters

Cited by 114 publications

References 32 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

Association of epidermal growth factor receptor mutations with human papillomavirus 16/18 E6 oncoprotein expression in non–small cell lung cancer

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

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