Original article
Allelic imbalance of HER2 variant in sporadic breast and ovarian cancer

https://doi.org/10.1016/j.cancergencyto.2004.09.023Get rights and content

Abstract

Both breast and ovarian cancers are associated with HER2 receptor activation, which usually results from receptor overexpression and/or gene amplification. The HER-2 gene harbors a polymorphism at codon 655 (GTC/valine to ATC/isoleucine) in the transmembrane domain region, which has been associated with an elevated risk of breast cancer. The objective of this study was to determine whether the polymorphism is under a selection pressure during breast and ovarian carcinogenesis. The Ile/Val genotype was present in 41% (9/22) of the normal DNA of breast cancer patients. An allelic imbalance in the tumor tissue was found in three breast tumors, with overrepresentation of the Val allele. HER-2 was amplified and overexpressed in these tumors. Half of the eight ovarian tumor patients carried heterozygous Ile/Val genotypes. In contrast to breast tumors, all these ovarian cancer specimens showed the presence of the Ile allele. In our selected set of tumors, the Val allele was overrepresented in the subset of HER2-positive breast cancers and the Ile allele in serous ovarian cancer. Further analyses of tumors with known gene amplifications and overexpression may reveal novel associations between germline polymorphisms and development of sporadic tumors.

Introduction

The HER2 oncogene belongs to the family of receptor tyrosine kinase type I and is strongly involved in breast cancer tumorigenesis. The mechanisms related to HER2 gene amplification, protein overexpression, and activation are complex and still inadequately understood. HER2 overexpression is frequently associated with gene amplification and is found in up to 20–30% of breast and ovarian cancers [1], [2]. At the present time, HER2 amplification is an established prognostic factor in breast cancer, and is associated with several clinico-pathologic features and a decreased survival time [3]. Due to its apparently important role in the genesis of some cancers, HER2 has become an attractive target for novel molecularly targeted therapies, e.g., Trastuzumab therapy [4], [5].

The driving force for transmembrane signaling via receptor tyrosine kinases is the process of ligand-induced receptor dimerization. HER2 is unique among the HER2 family of receptors because it lacks a specific ligand. HER2 serves as a heterodimerization partner for other members of the HER family. These heterodimers are long-lived and further enhance cell signaling. In animal models, a point mutation altering the transmembrane domain of the rat neu gene converts the normal gene into a potent oncogene [6]. A corresponding mutation, however, has not been identified in human tumors.

The sequence analysis of human HER2 has identified a polymorphism in the transmembrane coding region at codon 655 that encodes either for isoleucine (ATC) or valine (GTC). The homo- or heterozygous Val genotype is associated with an increased risk of breast cancer, particularly among younger women with a positive familial history [7], [8], [9]. It is not known how this variant contributes to the risk of developing sporadic breast cancer.

In the study, we examined the relationship of HER2 expression, gene amplification, and the HER2 genotype in sporadic breast and ovarian tumors. All tumors subjected to analysis had corresponding normal tissue available for determining the stem line HER2 genotype and identifying possible alterations in the tumor genotype during tumorigenesis.

Section snippets

Tissue material

The samples came from the well–characterized breast and serous ovarian carcinoma materials whose gene amplification and protein expression status was known from previous studies [10], [11]. Both amplification and/or overexpression-positive and -negative samples were included in this study. For breast and ovarian carcinomas, more than five gene copies per nucleus were regarded as high-level amplifications. Normal DNA availability was also a selection criterion for tumor selection. Twenty-nine

HER2 genotype analysis in breast cancer

The tumor tissue genotypes could be determined in 27 (100%) of the breast tumors and in 22 (81.5%) of the normal breast tissue samples available. The Ile/Val genotype was present in nine (40.9%) of the normal tissue samples and in nine tumor samples (33.3%) (Fig. 1; Table 1). Comparison of the normal and tumor tissue genotypes revealed an additional change of Ile/Val to Val/Val in three of the nine Ile/Val cases. The breast cancer tumors with the Val/Val genotype expressed HER2 and harbored HER2

Discussion

The HER2 proto-oncogene was cloned 20 years ago and its clinical relevance is widely recognized today. HER2 overexpression is detected in various types of human cancer, especially in ovarian and breast cancers. Its overexpression is associated with a poor clinical outcome, particularly in node-positive cases [2], [15]. It has been established that HER2 overexpression is a critical step for the initiation and progression of breast cancer. Some tumors deficient in HER2 amplification show

Acknowledgments

The authors thank Ms. Gynel Arifdshan and Laura Pulli for their skillful technical assistance. This work is supported by grants from the Cancer Society of Finland, Foundation for the Finnish Cancer Institute, Helsinki University Research Grants, and the Sigrid Juselius Foundation.

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