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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    42 Scopus citations

    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 (US)
    Article numberddr597
    Pages (from-to)1665-1672
    Number of pages8
    JournalHuman molecular genetics
    Volume21
    Issue number7
    DOIs
    StatePublished - Apr 1 2012

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)

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    Kiyotani, K., Mushiroda, T., Tsunoda, T., Morizono, T., Hosono, N., Kubo, M., Tanigawara, Y., Imamura, C. K., Flockhart, D. A., 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, 21(7), 1665-1672. [ddr597]. https://doi.org/10.1093/hmg/ddr597