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Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, Shen H, Park SK, Chen K, Shen CY, Ren Z, Haiman CA, Matsuo K, Kim MK, Khoo US, Iwasaki M, Zheng Y, Xiang YB, Gu K, Rothman N, Wang W, Hu Z, Liu Y, Yoo KY, Noh DY, Han BG, Lee MH, Zheng H, Zhang L, Wu PE, Shieh YL, Chan SY, Wang S, Xie X, Kim SW, Henderson BE, Le Marchand L, Ito H, Kasuga Y, Ahn SH, Kang HS, Chan KY, Iwata H, Tsugane S, Li C, Shu XO, Kang DH, Zheng W - PLoS Genet. (2012)

Bottom Line: Genetic factors play an important role in the etiology of both sporadic and familial breast cancer.Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G.SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.

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Overview of the study design.
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pgen-1002532-g001: Overview of the study design.

Mentions: A total of 19,091 female breast cancer cases and 20,606 female controls—including 23,891 Chinese, 11,907 Korean and 3,809 Japanese women—were included in the present study (Table 1). In Stage I, we analyzed 690,947 SNPs in 2,918 breast cancer cases and 2,324 community controls recruited from studies conducted in Shanghai, China (Figure 1, Text S1). Top 5,365 SNPs were investigated in Stage IIa including 1,613 Chinese cases and 1,800 Chinese controls recruited from studies conducted in Shanghai, China. Of the SNPs evaluated, 68 SNPs showed an association with breast cancer risk at P≤0.05 with the same direction as observed in Stage I. We performed a meta-analysis for the remaining 4,913 SNPs with data available from both Stage IIa and Stage IIb (2,359 Korean cases and 2,052 Korean controls). Twenty-six SNPs showed an association with breast cancer risk with Pmeta≤0.05 and the association was consistent among Stages I, IIa and IIb. These SNPs, along with the 68 SNPs mentioned above, were selected for Stage III replication in 4,712 cases and 4,496 controls. Finally, based on the results of the first three stages, 22 top SNPs were selected for Stage IV evaluation in 7,489 cases and 9,934 controls.


Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, Shen H, Park SK, Chen K, Shen CY, Ren Z, Haiman CA, Matsuo K, Kim MK, Khoo US, Iwasaki M, Zheng Y, Xiang YB, Gu K, Rothman N, Wang W, Hu Z, Liu Y, Yoo KY, Noh DY, Han BG, Lee MH, Zheng H, Zhang L, Wu PE, Shieh YL, Chan SY, Wang S, Xie X, Kim SW, Henderson BE, Le Marchand L, Ito H, Kasuga Y, Ahn SH, Kang HS, Chan KY, Iwata H, Tsugane S, Li C, Shu XO, Kang DH, Zheng W - PLoS Genet. (2012)

Overview of the study design.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285588&req=5

pgen-1002532-g001: Overview of the study design.
Mentions: A total of 19,091 female breast cancer cases and 20,606 female controls—including 23,891 Chinese, 11,907 Korean and 3,809 Japanese women—were included in the present study (Table 1). In Stage I, we analyzed 690,947 SNPs in 2,918 breast cancer cases and 2,324 community controls recruited from studies conducted in Shanghai, China (Figure 1, Text S1). Top 5,365 SNPs were investigated in Stage IIa including 1,613 Chinese cases and 1,800 Chinese controls recruited from studies conducted in Shanghai, China. Of the SNPs evaluated, 68 SNPs showed an association with breast cancer risk at P≤0.05 with the same direction as observed in Stage I. We performed a meta-analysis for the remaining 4,913 SNPs with data available from both Stage IIa and Stage IIb (2,359 Korean cases and 2,052 Korean controls). Twenty-six SNPs showed an association with breast cancer risk with Pmeta≤0.05 and the association was consistent among Stages I, IIa and IIb. These SNPs, along with the 68 SNPs mentioned above, were selected for Stage III replication in 4,712 cases and 4,496 controls. Finally, based on the results of the first three stages, 22 top SNPs were selected for Stage IV evaluation in 7,489 cases and 9,934 controls.

Bottom Line: Genetic factors play an important role in the etiology of both sporadic and familial breast cancer.Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G.SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.

Show MeSH
Related in: MedlinePlus