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Title: Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer}
Article:
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.
Introduction:
Breast cancer is one of the most common malignancies diagnosed among women worldwide, including those living in East Asian countries. Genetic factors play an important role in the etiology of both sporadic and familial breast cancer[1]. In the past two decades, more than 1, 000 reports have been published addressing the association between variants in candidate genes and breast cancer risk. However, only a few genetic risk factors have been confirmed for this common malignancy[2]. Recent genome-wide association studies( GWAS) have identified approximately 20 common genetic susceptibility loci for breast cancer[3]–[14]. However, these newly-identified genetic factors, along with known high-penetrance breast cancer susceptibility genes explain less than 30% of the heritability for this cancer[2],[15]. Furthermore, most GWAS were conducted among women of European ancestry, and many of the variants discovered in European-ancestry populations showed only a weak or no association with breast cancer in other ethnic groups[16],[17]. For example, only 8 of 12 breast cancer risk SNPs identified in women of European ancestry were directly replicated in Chinese population[18]. Therefore, GWAS conducted in non-European women are needed to fully uncover the genetic basis for breast cancer susceptibility. Herein, we report results from a large GWAS of breast cancer conducted in East Asian women.
Discussion:
In this large GWAS conducted in East-Asian women including 19, 091 cases and 20, 606 controls, we provided strong evidence for a novel breast cancer susceptibility locus represented by rs9485372 and suggestive evidence for two other loci, represented by SNPs rs9383951 and rs7107217. We previously reported a genetic susceptibility locus at 6q25. 1, represented by rs2046210, for breast cancer risk[8]. The newly identified SNPs, rs9485372 and rs9383951, also are located at chromosome 6q25. 1. However, these three SNPs are not in LD and are thus representing independent breast cancer susceptibility loci. All of them were associated with breast cancer risk after mutual adjustment of the other two SNPs. SNP rs9485372 is approximately 31 Kb upstream of the TGF-β activated kinase 1/MAP3K7 binding protein 2( TAB2) gene( Figure 3). The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for the IL-1 induced activation of NF-κB and MAPK8/JNK. The TGF-β pathway plays a major role in breast cancer development and progression[19]. The MAP kinases pathway is critical in regulating cell growth and cell death[20] and may contribute to the development of cancer[20]. Furthermore, the TAB2 protein is required for DNA damage-induced TAK1 activation, suggesting that TAB2 may play a role in DNA damage repair[21]. Other genes in the region identified in the study included SUMO4, LATS1, PPIL4, and UST. However, given the proximity of the TAB2 gene with rs9485372 and the important role of this gene in breast carcinogenesis, it is possible that the association between rs9485372 and breast cancer risk may be mediated through the TAB2 gene. It is also possible that the association may be mediated through regulating the ESR1 gene, located approximately 2. 5 Mb from rs9485372. This possibility was highlighted by a recent study showing that several open reading frames in the 6q25. 1 regions co-expressed with ESR1[22]. Further research is warranted to clarify the mechanism of the association identified in the study. SNP rs9383951 is located in intron 5 of the ESR1 gene, an important gene that has been documented to play a key role in breast cancer development and progression. Previous candidate gene studies have extensively evaluated two SNPs, rs2234693( Pvull) and rs9340799( XbaI), in the ESR1 gene in relation to breast cancer risk; the results, however, have been inconsistent[2]. Neither rs2234693 nor rs9340799 are in LD( r2<0. 01) with the SNPs discovered in the present study. To follow-up the lead from our previous study reporting a susceptibility locus at 6q25. 1 for breast cancer[8], two recent studies conducted among women of European descent identified rs3757318 and rs9397435 in relation to breast cancer risk[11],[23]. These two SNPs are in strong LD( r2>0. 6 in Asians) with the SNP( rs2046210) we previously reported at 6q25. 1 in East Asians but not in other populations. Again, these two SNPs are not in LD( r2<0. 01 in Asian, European and African populations) with rs9383951 and rs9485372 identified in this study. Although the association with rs9383951 did not reach the conventional genome-wide significance, the fact that this SNP is located in the ESR1 gene strongly suggests a true association of this SNP with breast cancer risk. SNP rs7107217 also showed a consistent association in all four stages, although the pooled P-value did not reach the conventional genome-wide significance level. This SNP is located at 11q24. 3, 152 Kb downstream of the BARX2 gene and 212 Kb upstream of the TMEM45B gene( Figure S3). BARX2 is a homeobox gene for which the mouse ortholog has been shown to influence cellular processes that control cell adhesion and cytoskeleton remodeling. It has been shown, BARX2 and estrogen receptor-alpha( ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion[24]. BARX2 also acts in a tumor suppressor and loss of heterozygosity of this gene, lead to poorer survival in patients with ovarian cancer[25]. It could be ideal to increase the sample size in the discovery stage and simplify the replication stages of the study. However, like many other consortium projects, financial constraints and some logistical issues prevented us for achieving the maximum statistical power. Nevertheless, with approximately 40, 000 cases and controls, our study represents the largest breast cancer genetic association study in East Asian women. This consortium will continue to provide valuable resources to identify additional novel susceptibility loci for breast cancer. In summary, in this large GWAS conducted in East Asia women, we provided convincing evidence for an association with a novel independent susceptibility locus located at 6q25. 1, near the TAB2 gene. Our study also suggests that genetic variants in the ESR1 gene and chromosome 11q24. 3 may be related to breast cancer risk. Given that multiple independent breast cancer susceptibility loci have identified in our studies and studies conducted by others in 6q25. 1 that harbors the ESR1 gene, it is possible that 6q25. 1 may represent an important region for breast cancer susceptibility.
Breast cancer is one of the most common malignancies among women worldwide . Genetic factors play an important role in the etiology of breast cancer . To identify common genetic susceptibility alleles for breast cancer , we performed a four-stage genome-wide association study in 19 , 091 cases and 20 , 606 controls among East-Asian women . Single nucleotide polymorphism ( SNP ) rs9485372 , near the TGF-beta activated kinase 1 ( TAB2 ) gene at chromosome 6q25 . 1 , was associated with breast cancer risk ( P = 3 . 8×10−12 ) . SNPs rs9383951 , located in intron 5 of the estrogen receptor 1 ( ESR1 ) gene , and rs7107217 , located at 11q24 . 3 , were also consistently associated with breast cancer risk in all four stages with a combined P of 1 . 9×10−6 and 4 . 6×10−7 , respectively . 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 .