title: Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression.
abstract: Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the epidermal growth factor receptor (EGFR) in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear. We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and eight malignant) by means of egfr fluorescence in situ hybridization (FISH) and gene dosage PCR for a regulatory sequence within intron 1 of egfr. Immunohistochemical staining was performed for EGFR, p16, p21, p27, p53, c-myc, Cyclin A, Cyclin D1, Cyclin E, c-kit and Ki67. Immunopositivity for EGFR was detected in 19% of phyllodes tumors (75% of all malignant tumors) in stromal tumor cells but not in the epithelial component. Whole-gene amplifications were seen by FISH in 15.8% (in stromal cells only) and intron 1 amplifications by gene dosage PCR in as much as 41.8% of all phyllodes tumors. Significant correlations were seen between tumor grade on the one hand and EGFR overexpression (P=0.001) and intron 1 amplifications (P<0.05) on the other. EGFR overexpression further correlated positively with immunohistochemical staining for p53, p16, Cyclin A, Cyclin E, Ki67 and c-kit. Presence of intron 1 amplifications correlated with p16 (P<0.01), p21 (P=0.009) and p53 immunoreactivity (P<0.001). Neither EGFR overexpression nor whole-gene amplification was observed in a control series of 167 fibroadenomas and only one of 43 (2.3%) exhibited intron 1 amplification in gene dosage PCR. In conclusion, our results show for the first time that activating mutations in and overexpression of egfr are associated with the progression in grade of phyllodes tumors of the breast. The observed association between intron 1 amplification and overexpression of EGFR provides further insight into regulation mechanisms of EGFR overexpression.
authors.affiliation: Institute of Pathology, University of Muenster, Muenster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kersting
authors.forename: Arno
authors.initials: A
authors.lastname: Kuijper
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Jens
authors.initials: J
authors.lastname: Packeisen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
authors.forename: Nicola
authors.initials: N
authors.lastname: Tidow
authors.forename: Christian
authors.initials: C
authors.lastname: Gustmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Hinrichs
authors.forename: Pia
authors.initials: P
authors.lastname: Wülfing
authors.forename: Joke
authors.initials: J
authors.lastname: Tio
authors.forename: Werner
authors.initials: W
authors.lastname: Boecker
authors.forename: Paul
authors.initials: P
authors.lastname: van Diest
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
authors.forename: Horst
authors.initials: H
authors.lastname: Buerger
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D003557:Phyllodes Tumor / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D066246:ErbB Receptors