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.
OBJECTIVE
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.


METHODS
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.
Han
Wonshik
W
Department of Surgery, Seoul National University College of Medicine, and DNA Link Inc., Seoul, Korea.
Kang
Daehee
D
Lee
Jong Eun
JE
Park
In Ae
IA
Choi
Ji-Yeob
JY
Lee
Kyung-Mu
KM
Bae
Ji Yeon
JY
Kim
Sook
S
Shin
Eun-Soon
ES
Lee
Jeong Eon
JE
Shin
Hyuk-Jae
HJ
Kim
Seok Won
SW
Kim
Sung-Won
SW
Noh
Dong-Young
DY
D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007723:Korea; D015810:Linkage Disequilibrium; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
D018719:Erb-b2 Receptor Tyrosine Kinases