Browsing by Author "Shen, Fei"
Now showing 1 - 10 of 17
Results Per Page
Sort Options
Item A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes(Springer Nature, 2022-11-22) Wu, Xi; Shen, Fei; Jiang, Guanglong; Xue, Gloria; Philips, Santosh; Gardner, Laura; Cunningham, Geneva; Bales, Casey; Cantor, Erica; Schneider, Bryan Paul; Medicine, School of MedicineAnthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone’s protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.Item Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology(Elsevier, 2019) Swart, Marelize; Stansberry, Wesley M.; Pratt, Victoria M.; Medeiros, Elizabeth B.; Kiel, Patrick J.; Shen, Fei; Schneider, Bryan P.; Skaar, Todd C.; Medical and Molecular Genetics, School of MedicineThe Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.Item Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial(American Medical Association, 2020-09) Radovich, Milan; Jiang, Guanglong; Hancock, Bradley A.; Chitambar, Christopher; Nanda, Rita; Falkson, Carla; Lynce, Filipa C.; Gallagher, Christopher; Isaacs, Claudine; Blaya, Marcelo; Paplomata, Elisavet; Walling, Radhika; Daily, Karen; Mahtani, Reshma; Thompson, Michael A.; Graham, Robert; Cooper, Maureen E.; Pavlick, Dean C.; Albacker, Lee A.; Gregg, Jeffrey; Solzak, Jeffrey P.; Chen, Yu-Hsiang; Bales, Casey L.; Cantor, Erica; Shen, Fei; Storniolo, Anna Maria V.; Badve, Sunil; Ballinger, Tarah J.; Chang, Chun-Li; Zhong, Yuan; Savran, Cagri; Miller, Kathy D.; Schneider, Bryan P.; Medical and Molecular Genetics, School of MedicineImportance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. Design, setting, and participants: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months). Interventions: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device. Main outcomes and measures: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Results: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). Conclusions and relevance: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials.Item Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients(Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of MedicineBackground: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. Results: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). Conclusions: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.Item Charcot-Marie-Tooth gene, SBF2, associated with taxaneinduced peripheral neuropathy in African Americans(Impact Journals, 2016-12-13) Schneider, Bryan P.; Lai, Dongbing; Shen, Fei; Jiang, Guanglong; Radovich, Milan; Li, Lang; Gardner, Laura; Miller, Kathy D.; O’Neill, Anne; Sparano, Joseph A.; Xue, Gloria; Foroud, Tatiana; Sledge Jr., George W.; Department of Medicine, IU School of MedicinePURPOSE: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. EXPERIMENTAL DESIGN: Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. RESULTS: Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. CONCLUSION: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.Item Correction: Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients(Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of MedicineCorrection to: British Journal of Cancer 10.1038/s41416-021-01557-w, published online 06 October 2021 The original version of this article unfortunately contained a mistake in an author affiliation. Dr. Kouros Owzar was listed as “Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA”, when it should be “Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA”. The original article has been corrected.Item Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103(American Association for Cancer Research, 2023) Shen, Fei; Jiang, Guanglong; Philips, Santosh; Gardner, Laura; Xue, Gloria; Cantor, Erica; Ly, Reynold C.; Osei, Wilberforce; Wu, Xi; Dang, Chau; Northfelt, Donald; Skaar, Todd; Miller, Kathy D.; Sledge, George W.; Schneider, Bryan P.; Medicine, School of MedicinePurpose: Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed. Experimental design: Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3-4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN. Results: Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10-6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN. Conclusions: Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.Item Discerning the clinical relevance of biomarkers in early stage breast cancer(Springer, 2017-07) Ballinger, Tarah J.; Kassem, Nawal; Shen, Fei; Jiang, Guanglong; Smith, Mary Lou; Railey, Elda; Howell, John; White, Carol B.; Schneider, Bryan P.; Department of Medicine, IU School of MedicinePurpose Prior data suggest that breast cancer patients accept significant toxicity for small benefit. It is unclear whether personalized estimations of risk or benefit likelihood that could be provided by biomarkers alter treatment decisions in the curative setting. Methods A choice-based conjoint (CBC) survey was conducted in 417 HER2-negative breast cancer patients who received chemotherapy in the curative setting. The survey presented pairs of treatment choices derived from common taxane- and anthracycline-based regimens, varying in degree of benefit by risk of recurrence and in toxicity profile, including peripheral neuropathy (PN) and congestive heart failure (CHF). Hypothetical biomarkers shifting benefit and toxicity risk were modeled to determine whether this knowledge alters choice. Previously identified biomarkers were evaluated using this model. Results Based on CBC analysis, a non-anthracycline regimen was the most preferred. Patients with prior PN had a similar preference for a taxane regimen as those who were PN naïve, but more dramatically shifted preference away from taxanes when PN was described as severe/irreversible. When modeled after hypothetical biomarkers, as the likelihood of PN increased, the preference for taxane-containing regimens decreased; similarly, as the likelihood of CHF increased, the preference for anthracycline regimens decreased. When evaluating validated biomarkers for PN and CHF, this knowledge did alter regimen preference. Conclusions Patients faced with multi-faceted decisions consider personal experience and perceived risk of recurrent disease. Biomarkers providing information on likelihood of toxicity risk do influence treatment choices, and patients may accept reduced benefit when faced with higher risk of toxicity in the curative setting.Item Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure(American Association for Cancer Research, 2017-01-01) Schneider, Bryan P.; Shen, Fei; Gardner, Laura; Radovich, Milan; Li, Lang; Miller, Kathy D.; Jiang, Guanglong; Lai, Dongbing; O’Neill, Anne; Sparano, Joseph A.; Davidson, Nancy E.; Cameron, David; Gradus-Pizlo, Irmina; Mastouri, Ronald A.; Suter, Thomas M.; Foroud, Tatiana; Sledge, George W., Jr.; Medicine, School of MedicinePURPOSE: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. EXPERIMENTAL DESIGN: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. RESULTS: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). CONCLUSIONS: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.Item Identification of a Genomic Region Between SLC29A1 and HSP90AB1 Associated With Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)(American Association for Cancer Research, 2019-10-01) Li, Megan; Mulkey, Flora; Jiang, Chen; O’Neil, Bert H.; Schneider, Bryan P.; Shen, Fei; Friedman, Paula N.; Momozawa, Yukihide; Kubo, Michiaki; Niedzwiecki, Donna; Hochster, Howard S.; Lenz, Heinz-Josef; Atkins, James N.; Rugo, Hope S.; Halabi, Susan; Kelly, William Kevin; McLeod, Howard L.; Innocenti, Federico; Ratain, Mark J.; Venook, Alan P.; Owzar, Kouros; Kroetz, Deanna L.; Medicine, School of MedicinePurpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.