Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Peer reviewe

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer

Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation.

BACKGROUND:The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM:The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS:Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS:Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION:From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system

Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation.

BACKGROUND:The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM:The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS:Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS:Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION:From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system