A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea

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Han, Wonshik; Kang, Daehee; Lee, Jong Eun; Park, In Ae; Choi, Ji-Yeob; Lee, Kyung-Mu; Bae, Ji Yeon; Kim, Sook; Shin, Eun-Soon; Lee, Jeong Eon; Shin, Hyuk-Jae; Kim, Seok Won; Kim, Sung-Won; Noh, Dong-Young
Issue Date
American Association for Cancer Research
Clin Cancer Res. 2005 Jul 1;11(13):4775-8
AdultAllelesBreast Neoplasms/genetics/metabolism/*pathologyCase-Control StudiesDisease-Free SurvivalFemaleGene FrequencyGenotypeHaplotypes/*geneticsHumansImmunohistochemistryKoreaLinkage DisequilibriumLymphatic MetastasisMiddle AgedNeoplasm Recurrence, LocalNeoplasm Staging*Polymorphism, Single NucleotidePrognosisReceptor, erbB-2/*genetics/metabolismRisk Factors
PURPOSE: A single-nucleotide polymorphism (SNP) in codon 655 of HER-2 has been extensively studied with inconclusive results. The purpose of this study was to investigate the association between common variants of HER-2 and breast cancer risk, HER-2 expression, and survival using a haplotype-based stepwise approach. EXPERIMENTAL DESIGN: Twenty-nine SNPs listed in the National Center for Biotechnology Information database were screened to identify novel polymorphisms of HER-2 gene in 90 healthy Korean women. Six of 29 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Using these six SNPs, linkage disequilibrium and haplotype patterns were characterized. We tested association between the haplotypes and breast cancer in a large case-control study (n=1,039 cases and 995 controls). Six-hundred two breast cancer patients with follow-up at least 24 months were analyzed for outcome in relation to haplotype. Expression of HER-2 protein was determined by immunohistochemistry in 1,094 cases of invasive breast cancer. RESULTS: All six SNPs showed a strong linkage disequilibrium pattern and were considered to belong to one haplotype block. Two haplotype-tagging SNPs (I655V and P1170A) for three common haplotypes (>5%) were genotyped in cases and controls. The haplotypes and individual SNPs were not associated with breast cancer risk. In patients with at least one copy of haplotype I (the most common haplotype), HER-2 expression was 1.5 times higher (P = 0.009) and the prognosis was worse (P = 0.032) compared with patients without having that haplotype. CONCLUSIONS: Our results suggest that the currently identified genetic polymorphisms of HER-2 are not associated with an increased risk of breast cancer in Korean women, whereas one haplotype does affect protein expression of the tumor and disease outcome.
1078-0432 (Print)
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College of Medicine/School of Medicine (의과대학/대학원)Surgery (외과학전공)Journal Papers (저널논문_외과학전공)
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