Dataset Information

Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.

ABSTRACT: Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor-positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor-negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.

SUBMITTER: Cuzick J

PROVIDER: S-EPMC5455424 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.

Cuzick Jack J Brentnall Adam R AR Segal Corrinne C Byers Helen H Reuter Caroline C Detre Simone S Lopez-Knowles Elena E Sestak Ivana I Howell Anthony A Powles Trevor J TJ Newman William G WG Dowsett Mitchell M

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20161228 7

Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were mat ...[more]

PMID: 28029312

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Project description:Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and African-American women. We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education. Our logistic regression identified 3 significant apoptosis-related SNPs in whites (APAF-1, rs1007573; CD40 rs3765459, and CD40 rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1, rs513349; TNF, rs1800629; TP63, rs6790167; TP63, rs7613791, TP63, rs35592567 and TP63, rs3856775) in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, APAF-1 (rs1007573), CD40 (rs3765459) and CD40 (rs1535045) were all found to be significant by FPRP. In African-Americans, TP63 SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI: 1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI: 3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and TP63 rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in African-Americans. In whites, only SNPs APAF-1 rs1007573 and CD40 rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only TP63 rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies.

Dataset Information

Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.

Publications

Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials.

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