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Our previous GWAS using samples from the NSABP P-1 and P-2 selective estrogen receptor modulator (SERM) breast cancer prevention trials identified SNPs in  ZNF423  and near  CTSO  that were associated with breast cancer risk during SERM chemoprevention. We have now performed Next Generation DNA sequencing to identify additional SNPs that might contribute to breast cancer risk and to extend our observation that SNPs located hundreds of bp from estrogen response elements (EREs) can alter estrogen receptor alpha (ERα) binding in a SERM-dependent fashion. Our study utilized a nested case-control cohort selected from patients enrolled in the original GWAS, with 199 cases who developed breast cancer during SERM therapy and 201 matched controls who did not. We resequenced approximately 500 kb across both  ZNF423  and  CTSO , followed by functional genomic studies. We identified 4079 SNPs across  ZNF423  and 3876 across  CTSO , with 9 SNPs in  ZNF423  and 12 in  CTSO  with  p  < 1E-02 that were within 500 bp of an ERE motif. The rs746157 ( p  = 8.44E-04) and rs12918288 SNPs ( p  = 3.43E-03) in intron 5 of  ZNF423 , were in linkage equilibrium and were associated with alterations in ER-binding to an ERE motif distant from these SNPs. We also studied all nonsynonymous SNPs in both genes and observed that one nsSNP in  ZNF423  displayed decreased protein expression. In conclusion, we identified additional functional SNPs in  ZNF423  that were associated with SNP and SERM-dependent alternations in ER binding and transcriptional regulation for an ERE at a distance from the SNPs, thus providing novel insight into mechanisms of SERM effect.

Breast cancer chemoprevention pharmacogenomics: Deep sequencing and functional genomics of the ZNF423 and CTSO genes