Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors

Nikuševa-Martić, Tamara; Beroš, Vili; Pećina‐Šlaus, Nives; Pećina, Hrvoje Ivan; Bulić-Jakuš, Floriana

doi:10.1016/j.prp.2007.07.009

Cited by 31 publications

(17 citation statements)

References 28 publications

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“…Annealing of mutant DNA to wild type probe gives duplexes with one or more mismatched bases (heteroduplexes). Mismatching causes the double helix to take on a conformation which retards its mobility during electrophoresis [50]. The results of our heteroduplex analysis did not demonstrate mutations of beta-catenin suggesting that mutations in exon 3 of the CTNNB1 gene are not associated to brain metastasis process.…”

Section: Discussionmentioning

confidence: 89%

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Kafka

Tomas

Beroš

et al. 2014

IJMS

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The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.

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Section: Discussionmentioning

confidence: 89%

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Kafka

Tomas

Beroš

et al. 2014

IJMS

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“…The suppression of E-cadherin expression is regarded as one of the main molecular events responsible for dysfunction of cell-cell adhesion (Schwecheimer et al, 1998). This is why the loss of E-cadherin is a well-known prerequisite for tumor cell invasion and metastasis formation (Nikuseva Martić et al, 2007). Since meningioma exhibits desmosomes (Schwecheimer et al, 1998), E-cadherin remains the main cadherin type adhesion molecule expressed in this tumor (Akat et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The correlation between E-cadherin expression and tumor grade in human meningiomas is fairly controversial (Brunner et al, 2006;Shimada et al, 2005). However, several recent studies demonstrated a decrease in E-cadherin expression as the histological grade increases (Nagaishi et al, 2012;Nikuseva Martić et al, 2007;Zhou et al, 2010). Contrary to E-cadherin, N-cadherin expression in tumor cells is regarded as a sign of invasive behavior (Hazan et al, 2004;Li et al, 2001;Wheelock and Jhonson, 2003).…”

Section: Discussionmentioning

confidence: 99%

Papillary meningioma in the dog: A clinicopathological case series study

Mandara

Reginato

Foiani

et al. 2015

Research in Veterinary Science

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“…Our interest in this project was mainly based on 3 findings: ( i ) Previous studies suggested that the activity of the Wnt pathway and β‐catenin protein level correlate with the malignancy grade of gliomas 12, 13. ( ii ) Even though genetic changes in Wnt components were found in a few gliomas, the frequency is too low to explain a common activation of Wnt signaling in these tumors 24, 25. ( iii ) Epigenetic inactivation of Wnt pathway inhibitors is a common way to induce Wnt signaling in other tumor types.…”

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confidence: 99%

Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas

Götze

Wolter

Reifenberger

et al. 2010

Intl Journal of Cancer

126

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Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the b-catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1-, SFRP5-, DKK1-, DKK3-, NKD1-and NKD2-hypermethylated U87-MG glioblastoma cells with 5-aza-2 0 -deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1-hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas.Gliomas are the most common primary brain tumors that are classified into 4 different malignancy grades according to the World Health Organization (WHO) classification. 1 Glioblastoma multiforme (GBM), the most common glioma, corresponds to WHO grade IV and clinically behaves as a highly malignant, rapidly fatal tumor, as indicated by a mean survival of less than 1 year in a population-based study. 2 Anaplastic astrocytomas (WHO grade III) are also malignant tumors with mean survival rates of 2-3 years after diagnosis.In contrast, diffuse astrocytomas of WHO grade II are considered as low-grade gliomas. However, these tumors have an inherent tendency for recurrence and malignant progression. Median survival is in the range of 6-8 years after diagnosis.Glioblastomas are divided into 2 distinct subtypes, 3 with primary glioblastoma (pGBM) accounting for more than 90% of the cases, usually affecting older patients and developing rapidly de novo without any obvious lower-grade precursor lesion. Genetically, pGBMs are characterized by frequent EGFR amplification, homozygous CDKN2A deletion and PTEN mutation. 4,5 In contrast, secondary glioblastomas (sGBMs) develop from preexisting lower-grade gliomas, preferentially occur in younger patients and often carry mutations in the IDH1 and T...

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Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors

Cited by 31 publications

References 28 publications

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

Papillary meningioma in the dog: A clinicopathological case series study

Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas

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