Mutation analysis of the p53, APC, and p16 genes in the Barrett's oesophagus, dysplasia, and adenocarcinoma.

González, Marı́a Victoria; Artímez, M L; Rodrigo, Luís; López‐Larrea, Carlos; Menéndez, M J; Álvarez, Victoria; Pérez, Ramón; Fresno, M F; Pérez, M J; Sampedro, Andrés Gené; Coto, Eliécer

doi:10.1136/jcp.50.3.212

Cited by 99 publications

(71 citation statements)

References 23 publications

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“…Just one of these was identified within a hotspot (codon 245), while those remaining were detected directly adjacent to the hotspot codons. The mutation frequency determined in this investigation was considerably lower than reported in the general literature; nevertheless, two other studies documented comparably lower p53 mutation frequencies of 8 and 12% (also at codon 245) (Casson et al, 1991;Gonzalez et al, 1997). It is unlikely that just examining exons 5 -8 missed many mutations, as 490% of the mutations documented in a wide range of tumours are found within this region (Hamelin et al, 1994;www.iarc.fr).…”

Section: Discussioncontrasting

confidence: 54%

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

et al. 2003

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p53 mutations and loss of heterozygosity have been commonly associated with oesophageal adenocarcinoma. In this investigation, the p53 status of a Welsh population of Barrett's-associated oesophageal adenocarcinomas were fully characterised at the gene sequence, chromosomal, mRNA and protein levels. In total, 31 tumours were examined for p53 gene sequence mutations using RFLP with sequencing, allelic loss of the gene was characterised by FISH, mRNA expression by p53 pathway signalling arrays and protein levels by p53 immunohistochemistry. In all, 9.6% of adenocarcinomas harboured p53 mutations, 24% displayed p53 allelic loss and 83% exhibited p53 protein accumulation. Point mutations and deletions of the gene did not coexist within the same samples. All samples containing p53 mutations also displayed positive immunostaining; however; in the majority of cases, p53 protein accumulation developed in the absence of mutations. The gene expression analysis demonstrated no differences in p53 and mdm-2 transcription levels between the p53 immunonegative and immunopositive samples, indicating other mechanisms underlie the proteins' overexpression. In conclusion, p53 mutations and deletions do not appear to be frequent events in oesophageal adenocarcinomas; however, abnormal accumulation of the protein is present in a vast majority of cases. P53 gene mutations are not the primary cause of protein overexpression -an alternative mechanism is responsible for the positive p53 immunohistochemistry detected.

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Section: Discussioncontrasting

confidence: 54%

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

et al. 2003

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“…Mutational analysis of some of the Wnt components including Axin, APC and b-catenin so far have identified very few genetic abnormalities in esophageal cancer, indicating that mechanisms other than mutations are responsible for activation of this pathway in esophageal cancer. [29][30][31] Figure 5 E-cadherin nuclear translocation was also found in primary colorectal cancer and metastasis. E-cadherin nuclear translocation was detected in primary colorectal cancers and in some areas of the corresponding liver metastasis of a colorectal tumor with nuclear E-cadherin (a).…”

Section: Discussionmentioning

confidence: 99%

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

et al. 2008

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Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 a/b (34%), Axin2 (48%), a-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of b-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but b-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion. Keywords: Wnt signaling; esophageal squamous cell carcinomas; pancreatic cancer; colon cancer; E-cadherin Esophageal cancer is one of the deadliest but least studied forms of cancer and the sixth ranking cause of death from cancer in North America. It shows a varied geographical distribution and very poor survival rates. 1 Esophageal cancer accounts for 5% of all gastrointestinal cancers, and the overall number of new cases each year is steadily increasing. 2 Esophageal cancer can be divided into squamous cell carcinomas and adenocarcinomas. So far, very few genetic abnormalities have directly been linked to esophageal carcinogenesis. In this study, we sought to examine the expression and localization of the key components of the Wnt signaling pathway that have previously been shown to play important roles in colorectal, breast, stomach and prostate cancer. Wnt signaling regulates cell growth, motility and differentiation. Upon binding to their receptor, specific Wnt ligands trigger phosphorylation of LRP5/6 (low density lipoprotein) by glycogen synthase kinase-3 (GSK3a/b) and casein kinase-1 (CK1g), which distances Axin (Axin1 and Axin2) from the b-catenin destruction-complex. [3][4][5][6] As a result, the b-catenin is stabilized a...

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“…A high incidence of LOH on the p arm of chromosome 17 and mutation of the P53 TSG at 17p13.1 are already well established features associated with the development of BOA, and there have been several studies reporting LOH frequencies at the P53 locus ranging from as high as 90 ± 100% (Gonzalez et al, 1997;Blount et al, 1994;Barrett et al, 1996b). Furthermore, in many tumours chromosome 17 is one of the most important targets of LOH and numerous studies testify to highly complex patterns of allelic imbalance a ecting many di erent regions of this chromosome (Cornelis et al, 1993;Phillips et al, 1993;Cropp et al, 1993;Nagai et al, 1995;Kirchweger et al, 1994;Kerangueven et al, 1997;Fong et al, 1995;Neideracher et al, 1997., Phelan et al, 1998.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic alterations involving the p53 TSG are amongst the most commonly found abnormality, present in many di erent tumours (Harris and Hollstein, 1993;Greenwald et al, 1992;Wang and Wang, 1996). In Barrett's oesophagus loss of heterozygosity (LOH), mutation and overexpression of the p53 TSG occurs frequently and in most cases precedes the development of invasive cancer (Gleeson et al, 1995;Krishnadath et al, 1995;Flejou et al, 1994;Casson et al, 1994;Blount et al, 1994;Galipeau et al, 1996;Audrezet et al, 1996;Campomenosi et al, 1996;Neshat et al, 1994;Gonzalez et al, 1997). Other genetic abnormalities found in BOA include LOH, homozygous deletion and mutation within the MTS1/p16 TSG at 9p21 (Gonzalez et al, 1997;Barrett et al, 1996a), LOH on 5q, 13q and 18q Blount et al, 1993), aneuploidy (Barrett et al, 1996b;Blount et al, 1994;Galipeau et al, 1996), and the ampli®cation and overexpression of certain oncogenes, notably c-erbB-2 and EGF-R. (Filipe and Jankowski, 1993;AlKasspooles et al, 1993;Nakamura et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Multiple target sites of allelic imbalance on chromosome 17 in Barrett's oesophageal cancer

et al. 1999

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Twelve Barrett's adenocarcinomas have been analysed for the occurrence of allelic imbalance (LOH) on chromosome 17 using 41 microsatellite markers. This study provides evidence for 13 minimal regions of LOH, six on 17p and seven on 17q. Four of these centre in the vicinity of the known tumour suppressor genes (TSGs) TP 53 (17p13.1), NF1 (17q11.2), BRCA1 (17q21.1), and a putative TSG (17p13.3). The tumours all displayed relatively small regions of LOH (1 ± 10 cM), and in several tumours extensive regions of LOH were detected. One tumour displayed only two very small regions of LOH; 17p11.2 and 17p13.1. The frequency of allelic imbalance has been calculated based on the LOH encompassing only one minimal region, and based on all the LOH observations. By both evaluations the highest LOH frequencies were found for regions II (p53), III (17p13.1 centromeric to p53), IV (17p12), V (17p11.2) and VII (NF1, 17q11.2). Our data supports the existence of multiple TSGs on chromosome 17 and challenges the view that p53 is the sole target of LOH on 17p in Barrett's adenocarcinoma.

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Mutation analysis of the p53, APC, and p16 genes in the Barrett's oesophagus, dysplasia, and adenocarcinoma.

Cited by 99 publications

References 23 publications

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Multiple target sites of allelic imbalance on chromosome 17 in Barrett's oesophageal cancer

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