Evidence for Association of SNPs in
ABCB1
and
CBR3
, but not
RAC2, NCF4, SLC28A3
or
TOP2B
, with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines
Abstract:with Aims: Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity. Patients & methods: A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and … Show more
“…Under our linear model of decline in LVEF, we observed a significant association of the CBR3 V244M variant in combined analyses of all patients (N=1,191), p=0.004, Beta=0.84 when A (Met) allele is reference 15,16 . We also observed association with the published ABCB1 variant rs2235047 (p=0.018) and a trend for association of rs17863783 variant in UGT1A6 (p=0.078).…”
Section: Resultsmentioning
confidence: 73%
“…Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites and polymorphisms in CBR1 and CBR3 influence the synthesis of these metabolites. CBR3 V244M was previously associated with a dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors 15 , and with cardiotoxicity in a cohort of breast cancer patients 16 . In a literature review entitled, âRecommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicityâ it was deemed that CBR3 required further validation.…”
Section: Discussionmentioning
confidence: 92%
“…Several SNPs have been associated with anthracycline-induced cardiotoxicity 16,19,20,27,28 . Under our linear model of decline in LVEF, we observed a significant association of the CBR3 V244M variant in combined analyses of all patients (N=1,191), p=0.004, Beta=0.84 when A (Met) allele is reference 15,16 .…”
Section: Resultsmentioning
confidence: 99%
“…To date, two common genetic polymorphisms within ERBB2 , Ile655Val and Pro1170Ala, have been associated with an increased risk of trastuzumab-related cardiotoxicity, but sample sizes were small (N ranging 61â140 patients) 10â14 . Polymorphisms in several genes including ABCB1 , CBR3 15,16 , RAC2 , NCF4 17,18 and SLC28A3 19,20 have been associated with anthracycline-related cardiotoxicity.…”
Objectives
The major clinical side-effect of the ERBB2 targeted breast cancer therapy, trastuzumab, is a decline in left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity.
Methods
The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or concurrent paclitaxel and trastuzumab (Arm C) in patients with HER2-positive breast cancer. A GWAS was performed on all patients with available DNA (N=1,446). We used linear regression to identify SNPs associated with decline in LVEF, adjusting for age, baseline LVEF, anti-hypertensive medications and the first two principle components.
Results
618,863 SNPs passed quality control (QC) and DNA from 1,191 patients passed genotyping QC and were identified as whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (p=7.73Ă10â6 to 8.93Ă10â8), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6 and LINC01060, in patients who received chemotherapy plus trastuzumab (Arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (Arm A, N=391) and did not increase in significance in analysis of all patients combined. We did not observe association, p<0.05 with SNPs previously associated with trastuzumab induced cardiotoxicity at ERBB2, I655V and P1170A. We replicated association, p<0.05, with SNPs previously associated with anthracycline cardiotoxicity at CBR3 and ABCB1.
Conclusions
Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.
“…Under our linear model of decline in LVEF, we observed a significant association of the CBR3 V244M variant in combined analyses of all patients (N=1,191), p=0.004, Beta=0.84 when A (Met) allele is reference 15,16 . We also observed association with the published ABCB1 variant rs2235047 (p=0.018) and a trend for association of rs17863783 variant in UGT1A6 (p=0.078).…”
Section: Resultsmentioning
confidence: 73%
“…Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites and polymorphisms in CBR1 and CBR3 influence the synthesis of these metabolites. CBR3 V244M was previously associated with a dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors 15 , and with cardiotoxicity in a cohort of breast cancer patients 16 . In a literature review entitled, âRecommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicityâ it was deemed that CBR3 required further validation.…”
Section: Discussionmentioning
confidence: 92%
“…Several SNPs have been associated with anthracycline-induced cardiotoxicity 16,19,20,27,28 . Under our linear model of decline in LVEF, we observed a significant association of the CBR3 V244M variant in combined analyses of all patients (N=1,191), p=0.004, Beta=0.84 when A (Met) allele is reference 15,16 .…”
Section: Resultsmentioning
confidence: 99%
“…To date, two common genetic polymorphisms within ERBB2 , Ile655Val and Pro1170Ala, have been associated with an increased risk of trastuzumab-related cardiotoxicity, but sample sizes were small (N ranging 61â140 patients) 10â14 . Polymorphisms in several genes including ABCB1 , CBR3 15,16 , RAC2 , NCF4 17,18 and SLC28A3 19,20 have been associated with anthracycline-related cardiotoxicity.…”
Objectives
The major clinical side-effect of the ERBB2 targeted breast cancer therapy, trastuzumab, is a decline in left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity.
Methods
The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or concurrent paclitaxel and trastuzumab (Arm C) in patients with HER2-positive breast cancer. A GWAS was performed on all patients with available DNA (N=1,446). We used linear regression to identify SNPs associated with decline in LVEF, adjusting for age, baseline LVEF, anti-hypertensive medications and the first two principle components.
Results
618,863 SNPs passed quality control (QC) and DNA from 1,191 patients passed genotyping QC and were identified as whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (p=7.73Ă10â6 to 8.93Ă10â8), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6 and LINC01060, in patients who received chemotherapy plus trastuzumab (Arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (Arm A, N=391) and did not increase in significance in analysis of all patients combined. We did not observe association, p<0.05 with SNPs previously associated with trastuzumab induced cardiotoxicity at ERBB2, I655V and P1170A. We replicated association, p<0.05, with SNPs previously associated with anthracycline cardiotoxicity at CBR3 and ABCB1.
Conclusions
Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.
“…Five studies included both children and adults in their report 36â39, 44 . Nineteen studies described the ethnicity of their participants 20, 23, 30â40, 43â45, 47, 50, 51 but, there were inconsistencies in reporting of race/ethnicity. For example, Weiss et al
33 described their participants either as Caucasian or not while Blanco et al
34 described their participants as White, Black and others.Figure 1PRISMA flow diagram showing the selection process and criteria of the included studies.
…”
Anthracyclines play an important role in the management of patients with cancer but the development of anthracycline-induced cardiotoxicity (ACT) remains a significant concern for most clinicians. Recently, genetic approach has been used to identify patients at increased risk of ACT. This systematic review assessed the association between genomic markers and ACT. A systematic literature search was performed in Medline, PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, AMED, EMBASE and HuGE Navigator from inception until May 2016. Twenty-eight studies examining the association of genetic variants and ACT were identified. These studies examined 84 different genes and 147 single nucleotide polymorphisms. Meta-analyses showed 3 risk variants significantly increased the risk for ACT; namely ABCC2 rs8187710 (pooled odds ratio: 2.20; 95% CI: 1.36â3.54), CYBA rs4673 (1.55; 1.05â2.30) and RAC2 rs13058338 (1.79; 1.27â2.52). The current evidence remains unclear on the potential role of pharmacogenomic screening prior to anthracycline therapy. Further research is needed to improve the diagnostic and prognostic role in predicting ACT.
BackgroundAnthracyclineârelated cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione Sâtransferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As freeâradical scavengers, GSTs could play a role in oxidative damageâinduced cardiomyopathy. Associations between the GSTÎŒ1 (GSTM1) null genotype and ironâoverloadârelated cardiomyopathy have been reported in patients with thalassemia.MethodsThe authors sought to identify an association between the GSTM1 null genotype and anthracyclineârelated cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and humanâinduced pluripotent stem cell cardiomyocytes (hiPSCâCMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative realâtime polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSCâCMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels.ResultsA significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3â5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 ± 0.57 vs 1.33 ± 1.33, respectively; P = .049). hiPSCâCMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007).ConclusionsThe current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracyclineârelated cardiomyopathy.
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