Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.
ABSTRACT Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. The Arg(388) allele was also found in cell lines derived from a variety of other tumor types as well as in the germ-line of cancer patients and healthy individuals. Analysis of three geographically separated groups indicated that it occurs in approximately 50% of the human population. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the Arg(388) allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was associated with early lymph node metastasis and advanced tumor-node-metastasis (TNM) stage in 82 colon cancer patients. Consistent with this finding, MDA-MB-231 mammary tumor cells expressing FGFR4 Arg(388) exhibited increased motility relative to cells expressing the FGFR4 Gly(388) isotype. Our results support the conclusion that the FGFR4 Arg(388) allele represents a determinant that is innocuous in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.
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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
- JNCI Journal of the National Cancer Institute 01/2001; 92(23):1947. · 14.34 Impact Factor
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ABSTRACT: Effective methods are needed to identify and isolate those genes that are differentially expressed in various cells or under altered conditions. This report describes a method to separate and clone individual messenger RNAs (mRNAs) by means of the polymerase chain reaction. The key element is to use a set of oligonucleotide primers, one being anchored to the polyadenylate tail of a subset of mRNAs, the other being short and arbitrary in sequence so that it anneals at different positions relative to the first primer. The mRNA subpopulations defined by these primer pairs were amplified after reverse transcription and resolved on a DNA sequencing gel. When multiple primer sets were used, reproducible patterns of amplified complementary DNA fragments were obtained that showed strong dependence on sequence specificity of either primer.Science 09/1992; 257(5072):967-71. · 31.03 Impact Factor