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. 2012 Mar 27;14(2):R56.
doi: 10.1186/bcr3158.

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study

Hyung-cheol Kim  1 , Ji-Young Lee, Hyuna Sung, Ji-Yeob Choi, Sue K Park, Kyoung-Mu Lee, Young Jin Kim, Min Jin Go, Lian Li, Yoon Shin Cho, Miey Park, Dong-Joon Kim, Ji Hee Oh, Jun-Woo Kim, Jae-Pil Jeon, Soon-Young Jeon, Haesook Min, Hyo Mi Kim, Jaekyung Park, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Min Hyuk Lee, Sung-Won Kim, Jong Won Lee, Byeong-Woo Park, Woong-Yang Park, Eun-Hye Kim, Mi Kyung Kim, Wonshik Han, Sang-Ah Lee, Keitaro Matsuo, Chen-Yang Shen, Pei-Ei Wu, Chia-Ni Hsiung, Jong-Young Lee, Hyung-Lae Kim, Bok-Ghee Han, Daehee Kang
Affiliations

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study

Hyung-cheol Kim et al. Breast Cancer Res. .

Abstract

Introduction: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent.

Methods: To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls.

Results: In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14).

Conclusions: This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.

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Figures

Figure 1
Figure 1
Manhattan plot for 555,525 genotyped single-nucleotide polymorphisms in 2,273 cases and 2,052 controls.
Figure 2
Figure 2
Forest plot. Result of pooled analysis of rs13393577 on the basis of estimated per-allele odds ratio from each stage. CI, confidence interval; ES, effect size.
Figure 3
Figure 3
Regional association plot of the 2q34 (rs13393577) locus. The results of association signals (-log P) are shown for directly genotyped (diamonds) and imputed (triangle) single-nucleotide polymorphisms (SNPs) distributed in a genomic region 500 kb to either side of rs1339577. Red reflects the linkage disequilibrium (r2) with the top SNP, and increasing red hue is associated with increasing r2. The blue bars show the recombination rate based on HapMap phase II release 22 JPT and CHB populations. The bottom panels illustrate the locations of known genes. The genomic position is based on the UCSC (University of California at Santa Cruz) Genome Browser assembly, March 2010. CHB, Han Chinese from Beijing; JPT, Japanese from Tokyo.
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