Global profiling of EGFR gene mutation, amplification, regulation and tissue protein expression in unknown primary carcinomas: to target or not to target?
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Dova, L.
Pentheroudakis, G.
Georgiou, I.
Malamou-Mitsi, V.
Vartholomatos, G.
Fountzilas, G.
Kolaitis, N.
Kitsiou, E.
Pavlidis, N.
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peer-reviewed
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Clin Exp Metastasis
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INTRODUCTION: Epidermal growth factor receptor (EGFR) signalling contributes to malignant transformation and survival. We studied molecular predictors of benefit from EGFR-modulating therapies in patients with cancer of unknown primary (CUP). MATERIALS AND METHODS: Tumours from paraffin-embedded biopsies of 50 patients with CUP were stained for EGFR protein by immunohistochemistry. Polymerase chain reaction amplification, single-strand conformational polymorphism and direct sequencing were used to study EGFR intron 1 cytosine-adenosine (CA) repeat length as well as exon 18, 19, 21 activating mutations and amplification. RESULTS: Thirty-seven tumours (74%) expressed EGFR protein but only six (12%) strongly. Regarding intron 1 CA repeat length, we detected five alleles with CA repeat numbers 16-20, allele 16 being the most common (39%). All samples were heterozygous, the commonest genotype consisting of 16/18 dinucleotides (78%). Five samples had three intron 1 alleles and were associated with EGFR overexpression in 40% of cases. There was no evidence of EGFR exon 18, 19, 21 amplification. Two mutations were detected: Exon 21 2508 C > T, a silent nucleotide polymorphism (R836R) and a G > A substitution in sequences flanking exon 19 (IVS19 + 24G > A) resulting in aberrant mRNA splicing. Neither EGFR protein expression nor CA repeat length were prognostic factors for survival. CONCLUSIONS: Our data depict absence of molecular predictors of benefit from EGFR modulation in patients with CUP. Study of its molecular pathophysiology and targeting other molecular pathways may be warranted instead.
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Aged, Aged, 80 and over, Base Sequence, DNA Primers, DNA, Neoplasm/genetics, Female, *Gene Expression Profiling, *Genes, erbB-1, Humans, Immunohistochemistry, Introns, Male, Middle Aged, Molecular Sequence Data, *Mutation, Neoplasm Proteins/*genetics, Neoplasms, Unknown Primary/*genetics, Polymerase Chain Reaction
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http://www.ncbi.nlm.nih.gov/pubmed/17390112
http://www.springerlink.com/content/u7872w40578304q4/fulltext.pdf
http://www.springerlink.com/content/u7872w40578304q4/fulltext.pdf
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en
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής