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Carcinogenesis Advance Access published online on November 18, 2004
Carcinogenesis, doi:10.1093/carcin/bgh342
© 2004 by Oxford University Press
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Received September 28, 2004
Revised November 10, 2004
Accepted November 14, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk

Bernd Frank 1*, Kari Hemminki 2, Michael Wirtenberger 1, Justo Lorenzo Bermejo 1, Peter Bugert 3, Rüdiger Klaes 4, Rita K. Schmutzler 5, Barbara Wappenschmidt 5, Claus R. Bartram 4, and Barbara Burwinkel 1

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden
3 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessia, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany
4 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
5 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Germany

* To whom correspondence should be addressed.
Bernd Frank, E-mail: b.frank{at}dkfz.de


  Abstract

Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20-30 % of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We tested eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, both adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. The case-controls study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of both Ile655Val (OR = 1.05, 95 % C.I. = 0.82-1.34, p = 0.728) and Ala1170Pro (OR = 0.94, 95 % C.I. = 0.74-1.20, p = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could not be detected either. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95 % C.I. = 1.08-6.08, p = 0.028). The rare Val654 is linked to the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654-Val655 allele provokes receptor dimerisation and activation thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict worse prognosis.


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