title: ERBB4 promoter polymorphism is associated with poor distant disease-free survival in high-risk early breast cancer.
abstract: A number of genetic variants have been linked to increased risk of breast cancer. Little is, however, known about the prognostic significance of hereditary factors. Here, we investigated the frequency and prognostic significance of two ERBB4 promoter region variants, -782G>T (rs62626348) and -815A>T (rs62626347), in a cohort of 1010 breast cancer patients. The frequency of nine previously described somatic ERBB4 kinase domain mutations was also analyzed. Clinical material used in the study consisted of samples from the phase III, adjuvant, FinHer breast cancer trial involving 1010 women. Tumor DNA samples were genotyped for ERBB4 variants and somatic mutations using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Paraffin-embedded tumor sections from all patients were immunohistochemically stained for ErbB4 expression. Association of ERBB4 genotype to distant disease-free survival (DDFS) was assessed using Kaplan-Meier and Cox regression analyses. Genotyping was successful for 91-93% of the 1010 samples. Frequencies observed for the ERBB4 variants were 2.5% and 1.3% for -782G>T and -815A>T, respectively. Variant -815A>T was significantly associated with poor survival (HR  = 2.86 [95% CI 1.15-6.67], P = 0.017). In contrast, variant -782G>T was associated with well-differentiated cancer (P = 0.019). Two (0.2%) ERBB4 kinase domain mutations were found, both of which have previously been shown to be functional and promote cancer cell growth in vitro. These data present the germ-line ERBB4 variant -815A>T as a novel prognostic marker in high-risk early breast cancer and indicate the presence of rare but potentially oncogenic somatic ERBB4 mutations in breast cancer.
authors.affiliation: Department of Medical Biochemistry and Genetics and Medicity Research Laboratories, University of Turku, Turku, Finland; Turku Doctoral Programme of Molecular Medicine, Turku, Finland.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Kurppa
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Rokavec
authors.affiliation: Department of Medical Biochemistry and Genetics and Medicity Research Laboratories, University of Turku, Turku, Finland; Department of Oncology, Turku University Hospital, Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Sundvall
authors.affiliation: Department of Oncology, Tampere University Hospital, Tampere, Finland.
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Department of Medical Biochemistry and Genetics and Medicity Research Laboratories, University of Turku, Turku, Finland; Department of Oncology, Turku University Hospital, Turku, Finland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4 / Q000737:chemistry / Q000235:genetics*
chemical_list: C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4