Breast cancer (BC) is the most common type of cancer diagnosed in women. Among female cancer deaths, BC is the second leading cause of death worldwide. For estrogen receptor-positive (ER-positive) breast cancers, endocrine therapy is an effective therapeutic approach. However, in many cases, an ER-positive tumor becomes unresponsive to endocrine therapy, and tumor regrowth occurs after treatment. While some genetic mutations contribute to resistance in some patients, the underlying causes of resistance to endocrine therapy are mostly undetermined. In this study, we utilized a recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes whose time course expression significantly change during cell modelling of endocrine resistant BC development. Expression of a subset of these genes was also differentially expressed in microarray analysis of endocrine-resistant and endocrine-sensitive tumor samples. Surprisingly, a subset of those genes was also differentially genes expressed in triple-negative breast cancer (TNBC) as compared with ER-positive BC. The findings suggest shared genetic mechanisms may underlie the development of endocrine resistant BC and TNBC. Our findings identify 34 novel genes for further study as potential therapeutic targets for treatment of endocrine-resistant BC and TNBC.
Introduction: Heart Failure (HF) has shared genetic architecture with its risk factors, including atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). The risk prediction performance of polygenic risk scores (PRS) for those HF risk factors and HF itself over an established risk equation warrants investigation. Methods: Within the Atherosclerosis Risk in Communities (ARIC) study, six PRSs were constructed for AF, BMI, CHD, SBP, T2D, and HF by summing the product of pre-computed weights from genome-wide association studies and SNP allele dosages in European and African Americans separately. The association between PRSs and incident HF was assessed using cox proportional hazard models, and the 10-, 20-, and 30-year risk prediction performance of PRS over the ARIC HF risk equation was assessed using C-statistics. Associations between AF PRS and HF subtypes, echocardiographic measures, and 4,877 proteins were examined. Results: Over 30 years follow-up, 1,922 (22%) and 735 (29%) HF cases developed in 8,624 European (mean age=54.2, 52% female) and 2,525 African (mean age=53.3, 61% female) Americans. The PRSs for AF and HF were associated with incident HF in both European and African Americans (P<0.05). The AF PRS showed the greatest effect on HF risk in European (HR=1.47, 95% CI: 1.41 to 1.53) and African (HR=1.29, 95% CI: 1.20 to 1.39) Americans. Addition of AF PRS to the ARIC HF risk equation significantly improved the C-statistics for 10-year risk prediction in European (ΔC=0.017, 95% CI: 0.009 to 0.026) and African (ΔC=0.015, 95% CI: 0.004 to 0.026) Americans. The AF PRS was further associated with HF with reduced (HR=1.45, 95% CI: 1.29 to 1.64) and preserved (HR=1.49, 95% CI: 1.34 to 1.66) ejection fraction, and higher left atrial volume index (P=1.67х10 -4 ). Protein analyses revealed that 61 proteins were associated with AF PRS, where NT-proBNP and Coagulation factor X showed the strongest positive and negative associations respectively. Conclusions: The PRS of AF was associated with incident HF, and had significant incremental value over an established HF risk prediction equation. These findings suggest that PRS may be useful in identifying individuals with high risk of HF.
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