Aberrant hypermethylation of the FGFR2 gene in human gastric cancer cell lines.
ABSTRACT We have previously shown that fibroblast growth factor receptor 2 (FGFR2) plays an important role in gastric carcinogenesis. In this study, we assessed DNA methylation status in the promoter region of FGFR2 gene in gastric cancer cell lines, and indicated that this region was highly methylated, compared with FGFR2-expressing gastric cancer cell lines. Moreover, the restoration of FGFR2 expression by treating methylated cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine strongly suggests that the loss of FGFR2 expression may be due to the aberrant hypermethylation in the promoter region of the FGFR2 gene. Thus, our results suggest that the epigenetic silencing of FGFR2 through DNA methylation in gastric cancer may contribute to tumor progression.
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ABSTRACT: Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.Advances in Cancer Research 02/1998; 72:141-96. · 6.35 Impact Factor
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ABSTRACT: Autosomal dominant disorders of skeletal and cranial development have been linked to fibroblast growth factor receptor (FGFR) 2 and FGFR3. Here we report two identical mutations in FGFR2 that cause craniosynostosis syndromes, Crouzon, Apert, and Pfeiffer in gastric carcinoma. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A-->G) in exon IIIc were detected in gastric cancer patients. Interestingly, these heterozygous somatic mutations are identical to the germinal activating mutations in FGFR2 reported previously in craniosynostosis syndromes. In addition, the two novel mutations of FGFR3 in colorectal carcinomas were identified. All identified mutations occurred at highly conserved sequences, not only in the FGFR family of molecules, but also throughout evolution and clustered in the immunoglobulin-like loop-III domain, highlighting the functional importance of this domain. Our results indicate that FGFR2 and FGFR3, in addition to their potential role in skeletal dysplasias, play an important role in tumorigenesis.Cancer Research 05/2001; 61(9):3541-3. · 8.65 Impact Factor
Article: Keratinocyte growth factor.[show abstract] [hide abstract]
ABSTRACT: Mucositis occurs in over 90% of patients undergoing stem cell transplantation for hematological malignancies. It is associated with significant morbidity in the form of pain, dysphagia and decreased oral intake, as well as mortality. Palifermin is a recombinant keratinocyte growth factor that has been shown to be effective in decreasing the incidence, severity and duration of mucositis in Phase III trials. Improvement in patient functioning during hematopoietic stem cell transplants has also been reported. This review deals with the preclinical data and the clinical trials that have been carried out with this agent in patients with hematologic malignancies. In addition limited Phase I and II data on solid tumors is available and will be included.Expert opinion on biological therapy 07/2009; 9(6):779-87. · 3.22 Impact Factor