A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese

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 singlenucleotide 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 5 2.87 3 10 -9 .9.4× 10 -8 ). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 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 (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P 5 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 5 2.28 × 10 -12 ).

Original languageEnglish
Article numberddr597
Pages (from-to)1665-1672
Number of pages8
JournalHuman molecular genetics
Volume21
Issue number7
DOIs
Publication statusPublished - 01-04-2012
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Tamoxifen
Breast Neoplasms
Survival
Recurrence
Therapeutics
Alleles
Genome
Genes
Cytochrome P-450 CYP2D6
Genetic Polymorphisms
Genotype
Hormones
Confidence Intervals

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kiyotani, Kazuma ; Mushiroda, Taisei ; Tsunoda, Tatsuhiko ; Morizono, Takashi ; Hosono, Naoya ; Kubo, Michiaki ; Tanigawara, Yusuke ; Imamura, Chiyo K. ; Flockhart, David A. ; Aki, Fuminori ; Hirata, Koichi ; Takatsuka, Yuichi ; Okazaki, Minoru ; Ohsumi, Shozo ; Yamakawa, Takashi ; Sasa, Mitsunori ; Nakamura, Yusuke ; Zembutsu, Hitoshi. / A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese. In: Human molecular genetics. 2012 ; Vol. 21, No. 7. pp. 1665-1672.
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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 singlenucleotide 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 5 2.87 3 10 -9 .9.4× 10 -8 ). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 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 (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95{\%} confidence interval (CI), 2.72-7.51; P 5 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 5 2.28 × 10 -12 ).",
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Kiyotani, K, Mushiroda, T, Tsunoda, T, Morizono, T, Hosono, N, Kubo, M, Tanigawara, Y, Imamura, CK, Flockhart, DA, Aki, F, Hirata, K, Takatsuka, Y, Okazaki, M, Ohsumi, S, Yamakawa, T, Sasa, M, Nakamura, Y & Zembutsu, H 2012, 'A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese', Human molecular genetics, vol. 21, no. 7, ddr597, pp. 1665-1672. https://doi.org/10.1093/hmg/ddr597

A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese. / Kiyotani, Kazuma; Mushiroda, Taisei; Tsunoda, Tatsuhiko; Morizono, Takashi; Hosono, Naoya; Kubo, Michiaki; Tanigawara, Yusuke; Imamura, Chiyo K.; Flockhart, David A.; Aki, Fuminori; Hirata, Koichi; Takatsuka, Yuichi; Okazaki, Minoru; Ohsumi, Shozo; Yamakawa, Takashi; Sasa, Mitsunori; Nakamura, Yusuke; Zembutsu, Hitoshi.

In: Human molecular genetics, Vol. 21, No. 7, ddr597, 01.04.2012, p. 1665-1672.

Research output: Contribution to journalArticle

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T1 - A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Tsunoda, Tatsuhiko

AU - Morizono, Takashi

AU - Hosono, Naoya

AU - Kubo, Michiaki

AU - Tanigawara, Yusuke

AU - Imamura, Chiyo K.

AU - Flockhart, David A.

AU - Aki, Fuminori

AU - Hirata, Koichi

AU - Takatsuka, Yuichi

AU - Okazaki, Minoru

AU - Ohsumi, Shozo

AU - Yamakawa, Takashi

AU - Sasa, Mitsunori

AU - Nakamura, Yusuke

AU - Zembutsu, Hitoshi

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N2 - 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 singlenucleotide 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 5 2.87 3 10 -9 .9.4× 10 -8 ). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 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 (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P 5 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 5 2.28 × 10 -12 ).

AB - 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 singlenucleotide 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 5 2.87 3 10 -9 .9.4× 10 -8 ). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 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 (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P 5 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 5 2.28 × 10 -12 ).

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