Abstract 2795: Replicating GWAS SNPs for breast cancer in Indian population
Authors: Nagrani Rajini T. , Mhatre Sharayu Sitaram , Badwe Rajendra , Dikshit Rajesh 
Published: August 2015

Background: There have been large Genome Wide Association Studies (GWAS) on breast cancer in most developed countries showing low to modest associations between common polymorphisms and breast cancer risk. In India, however, there have been no GWAS studies and few properly designed retrospective studies with smaller sample size on genetic susceptibility to study this risk.

Methodology: DNA was extracted from buffy coat samples in 1204 cases and 1212 control. A customized panel of 384 SNPs was designed using a mixture of 3 strategies such as SNPs selected from GWAS, SNPs selected from Candidate Studies and SNPs selected using Bioinformatics tool. Genotyping was performed on the Illumina Hi-Scan using GoldenGate Genotyping (GGGT) Custom SNP Panel assay on all DNA samples extracted. The reproducibility rate of all the replicate samples (n = 160) for all the assays was 99% and above. Unconditional logistic regression (additive model) was used to estimate OR and corresponding 95% CI between genotypes and case status. This abstract focuses on replicating SNPs in Indian population which have shown to be associated in already conducted GWAS mostly in developed nations.

Results: Seven SNPs were replicated from previous studies on BC GWAS. Prevalence of certain SNPs in the present study varied with that observed in GWAS. Out of 40 SNPs which did not show an association with BC, 15 SNPs had a MAF below 20% and 25 SNPs had prevalence of 20% and above.

The risk of SNPs which were significantly identified in BC GWAS and in present study were also studied in BCs stratified on hormone receptor status. The SNP rs2046210 in ESR1 showed an increased risk for BCs which were ER-/PR- and triple negative but not ER+/PR+. The SNPs rs10411161 in Zinc Finger Protein 577 (ZNF577) gene showed significant protection in the development of only ER+/PR+ BCs whereas SNPs in FGFR2 (rs2981575, rs2981582), Mitogen-Activated Kinase Kinase Kinase 1 (MAP3K1) (rs889312) and 9q31.2 (rs865686) increased the risk of hormone receptor positive BC.

Discussion: SNPs selected from FGFR2 gene were positively associated with BC. 25 SNPs which were identified as a risk factor for BC in the GWAS conducted in other populations did not replicate in the Indian population, even though their prevalence was high (≥ 20%) indicating that they may not be a risk factor in Indian population. The 3 SNPs which were highly prevalent in GWAS population could not be replicated even if they were associated the attributable risk of the SNPs remains low due to their low prevalence in the present study population. The SNPs associated with ER+/PR+ and ER-/PR- BCs were observed to be different suggesting that the cancer stratified on hormone receptor status may differ due to different biological pathways.

Citation Format: Rajini T. Nagrani, Sharayu Sitaram Mhatre, Rajendra Badwe, Rajesh Dikshit. Replicating GWAS SNPs for breast cancer in Indian population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2795. doi:10.1158/1538-7445.AM2015-2795