A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk
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MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78–0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70–0.98, P = 0.0314), whereas no significant effect was observed in the age group ≥ 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.
KeywordsBreast cancer risk MicroRNA SNP Case–control study
We thank Ludwig Heesen, Michelle Dick, Ying Wang, and Anja Schwaeger for their help in genotyping. We are grateful to Bowang Chen for statistical analysis as well as to Sandrine Tchatchou for the technical support. The German breast cancer samples were collected as a part of a project funded by the Deutsche Krebshilfe (Grant number: 107054). This study was supported by the Helmholtz society, the German Cancer Research Center (DKFZ), EU, LSHC-CT-2004-503465, and the Dietmar-Hopp Foundation.
- 27.Tchatchou S, Jung A, Hemminki K, Sutter C, Wappenschmidt B, Bugert P, Weber BH, Niederacher D, Arnold N, Varon-Mateeva R et al (2009) A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women. Carcinogenesis 30:59–64CrossRefPubMedGoogle Scholar
- 29.Kapeller J, Houghton LA, Monnikes H, Walstab J, Moller D, Bonisch H, Burwinkel B, Autschbach F, Funke B, Lasitschka F et al (2008) First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 17:2967–2977CrossRefPubMedGoogle Scholar
- 66.Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Hasegawa S, Takagi T, Wang FY et al (2007) A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dig Dis Sci 52:1691–1697CrossRefPubMedGoogle Scholar