title: A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.
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.
authors.affiliation: Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama 230-0045, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takashi
authors.initials: T
authors.lastname: Morizono
authors.forename: Naoya
authors.initials: N
authors.lastname: Hosono
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Fuminori
authors.initials: F
authors.lastname: Aki
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takatsuka
authors.forename: Minoru
authors.initials: M
authors.lastname: Okazaki
authors.forename: Shozo
authors.initials: S
authors.lastname: Ohsumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Sasa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10; D018572:Disease-Free Survival; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C000715087:ABCC2 protein, human; D018931:Antineoplastic Agents, Hormonal; D000089762:Multidrug Resistance-Associated Protein 2; D013629:Tamoxifen