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Seham Elgazzar,
Hitoshi Zembutsu,
Atsushi Takahashi,
Michiaki Kubo, Fuminori Aki,
Koichi Hirata,
Yuichi Takatsuka,
Minoru Okazaki,
Shozo Ohsumi,
Takashi Yamakawa,
Mitsunori Sasa,
Toyomasa Katagiri,
Yoshio Miki,
Yusuke Nakamura
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ABSTRACT: In Japan, breast cancer is the most common cancer among women and the second leading cause of cancer death among women worldwide. To identify genetic variants associated with the disease susceptibility, we performed a genome-wide association study (GWAS) using a total of 1086 Japanese female patients with hormonal receptor-positive (HRP) breast cancer and 1816 female controls. We selected 33 single-nucleotide polymorphisms (SNPs) with suggestive associations in GWAS (P-value of <1 × 10(-4)) as well as 4 SNPs that were previously implicated their association with breast cancer for further replication by an independent set of 1653 cases and 2797 controls. We identified significant association of the disease with a SNP rs6788895 (P(combined) of 9.43 × 10(-8) with odds ratio (OR) of 1.22) in the SIAH2 (intron of seven in absentia homolog 2) gene on chromosome 3q25.1 where the involvement in estrogen-dependent diseases was suggested. In addition, rs3750817 in intron 2 of the fibroblast growth factor receptor 2 gene, which was reported to be associated with breast cancer susceptibility, was significantly replicated with P(combined) of 8.47 × 10(-8) with OR=1.22. Our results suggest a novel susceptibility locus on chromosome 3q25.1 for a HRP breast cancer.Journal of Human Genetics advance online publication, 6 September 2012; doi:10.1038/jhg.2012.108.
Journal of Human Genetics 09/2012; · 2.57 Impact Factor
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Kazuma Kiyotani,
Taisei Mushiroda,
Tatsuhiko Tsunoda,
Takashi Morizono,
Naoya Hosono,
Michiaki Kubo,
Yusuke Tanigawara,
Chiyo K Imamura,
David A Flockhart, Fuminori Aki,
Koichi Hirata,
Yuichi Takatsuka,
Minoru Okazaki,
Shozo Ohsumi,
Takashi Yamakawa,
Mitsunori Sasa,
Yusuke Nakamura,
Hitoshi Zembutsu
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ABSTRACT: Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.
Human Molecular Genetics 12/2011; 21(7):1665-72. · 7.64 Impact Factor
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Kazuma Kiyotani,
Taisei Mushiroda,
Naoya Hosono,
Tatsuhiko Tsunoda,
Michiaki Kubo, Fuminori Aki,
Yutaka Okazaki,
Koichi Hirata,
Yuichi Takatsuka,
Minoru Okazaki,
Shozo Ohsumi,
Takashi Yamakawa,
Mitsunori Sasa,
Yusuke Nakamura,
Hitoshi Zembutsu
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ABSTRACT: We earlier reported a significant association between the cytochrome P450 2D6 (CYP2D6) genotype and the clinical outcome in 282 Japanese breast cancer patients receiving tamoxifen monotherapy. Although many research groups have provided evidence indicating the CYP2D6 genotype as one of the strongest predictors of tamoxifen response, the results still remain controversial. We hypothesized that concomitant treatment was one of the causes of these controversial results. We then studied 167 breast cancer patients who received tamoxifen-combined therapy to evaluate the effects of concomitant treatment on the association analysis and observed no significant association between CYP2D6 genotype and recurrence-free survival (P=0.44, hazard ratio: 0.64, 95% confidential interval: 0.20-1.99 in patients with two variant alleles vs. patients without a variant allele). When we carried out two subgroup analyses for nodal status and tumor size, we observed a positive association between the CYP2D6 genotype and the clinical outcome only in patients who received tamoxifen monotherapy. This study explained a part of the discrepancies among the reported results.
Pharmacogenetics and Genomics 09/2010; 20(9):565-8. · 3.48 Impact Factor
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Kazuma Kiyotani,
Taisei Mushiroda,
Chiyo K Imamura,
Naoya Hosono,
Tatsuhiko Tsunoda,
Michiaki Kubo,
Yusuke Tanigawara,
David A Flockhart,
Zeruesenay Desta,
Todd C Skaar, Fuminori Aki,
Koichi Hirata,
Yuichi Takatsuka,
Minoru Okazaki,
Shozo Ohsumi,
Takashi Yamakawa,
Mitsunori Sasa,
Yusuke Nakamura,
Hitoshi Zembutsu
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[hide abstract]
ABSTRACT: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen.
We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d.
CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with <or= one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups.
Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.
Journal of Clinical Oncology 03/2010; 28(8):1287-93. · 18.37 Impact Factor
