Yi-Chen Hsieh1, Er-Chieh Cho2, Shih-Hsin Tu3,4,5, Chih-Hsiung Wu6, Chin-Sheng Hung5,7, Mao-Chih Hsieh8, Chien-Tien Su9,10, Yun-Ru Liu11, Chia-Hwa Lee12, Yuan-Soon Ho12, Hung-Yi Chiou13. 1. Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 2. Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. 3. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 4. Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. 5. Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan. 6. Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan. 7. Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan. 8. Department of Surgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan. 9. School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. 10. Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 11. Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan. 12. Graduate Institute of Medical Sciences, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 13. School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. hychiou@tmu.edu.tw.
Abstract
BACKGROUND: Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. METHODS: This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. RESULTS: Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1-3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. CONCLUSIONS: A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.
BACKGROUND: Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. METHODS: This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. RESULTS: Logistic regression analysis showed that individuals with the MSH2rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1-3.8), particularly in early-onset breast cancerpatients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. CONCLUSIONS: A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.