title: Polymorphism rs4919510:C>G in mature sequence of human microRNA-608 contributes to the risk of HER2-positive breast cancer but not other subtypes.
abstract: BACKGROUND
  A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility.
  
  
  METHODS
  The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism.
  
  
  RESULTS
  In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34-2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23-2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43-2.72) for GG genotype (corrected P = 1.1 × 10(-4)). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is -35.9 kcal/mol, while that of variant-form (G-allele) is -31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA.
  
  
  CONCLUSIONS
  rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation.
authors.affiliation: Department of Breast Surgery, Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: A-Ji
authors.initials: AJ
authors.lastname: Huang
authors.forename: Ke-Da
authors.initials: KD
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Fan
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D000076249:Heat Shock Transcription Factors; D006801:Humans; D016015:Logistic Models; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C000619706:HSF1 protein, human; C508053:ERBB2 protein, human