Browsing by Author "Mushiroda, Taisei"

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    Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors
    (National Comprehensive Cancer Network, 2019-05-01) Abu Zaid, Mohammad; Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; El-Charif, Omar; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Sesso, Howard D.; Huddart, Robert; Mushiroda, Taisei; Kubo, Michiaki; Dolan, M. Eileen; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Platinum Study Group; Medicine, School of Medicine
    Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P=.006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P=.011) or ≥30 kg/m2 (OR, 2.36; P=.005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P=.09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P=.07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P=.003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P=.013), and to report erectile dysfunction (19.6% vs 11.9%; P=.018) or peripheral neuropathy (30.7% vs 22.5%; P=.041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P=.07) or anxiety/depression (14.8% vs 9.3%; P=.06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.
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    Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms
    (American Association for Cancer Research, 2019-07-01) Charif, Omar El; Mapes, Brandon; Trendowski, Matthew R.; Wheeler, Heather E.; Wing, Claudia; Dinh, Paul C.; Frisina, Robert D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Gamazon, Eric R.; Cox, Nancy J.; Huddart, Robert; Ardeshir-Rouhani-Fard, Shirin; Monahan, Patrick; Fossa, Sophie D.; Einhorn, Lawrence H.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of Medicine
    Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n= 762) were dichotomized to cases (moderate/severe tinnitus; n=154) and controls (none; n=608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in GWAS following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P=0.007) and cumulative cisplatin dose (P=0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared to 300 (P=0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P<0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P<0.0001), and reported more vertigo (OR=6.47; P<0.0001) and problems hearing in a crowd (OR=8.22; P<0.0001) than controls. Cases reported poorer health (P=0.0005) and greater psychotropic medication use (OR=2.4; P=0.003). GWAS suggested a variant near OTOS (rs7606353, P=2×10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P=0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q=0.007). Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
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    Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy
    (American Association for Cancer Research, 2019-10-01) Trendowski, Matthew R.; El Charif, Omar; Ratain, Mark J.; Monahan, Patrick; Mu, Zepeng; Wheeler, Heather E.; Dinh, Paul C., Jr.; Feldman, Darren R.; Ardeshir-Rouhani-Fard, Shirin; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Hannigan, Robyn; Strathmann, Frederick; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of Medicine
    Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13×10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58×10−3). Patients with high residual platinum levels experienced greater Raynaud’s phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6×10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
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    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update
    (Wiley, 2016-01) Saito, Yoshiro; Stamp, Lisa K.; Caudle, Kelly E.; Hershfield, Michael; McDonagh, Ellen M.; Callaghan, John T.; Tassaneeyakul, Wichittra; Mushiroda, Taisei; Kamatani, Naoyuki; Goldspiel, Barry R.; Phillips, Elizabeth J.; Klein, Teri E.; Lee, Ming Ta Michael; Department of Pharmacology and Toxicology, IU School of Medicine
    The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).
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    Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy
    (Wiley, 2020-09) Chua, Katherina C.; Xiong, Chenling; Ho, Carol; Mushiroda, Taisei; Jiang, Chen; Mulkey, Flora; Lai, Dongbing; Schneider, Bryan P.; Rashkin, Sara R.; Witte, John S.; Friedman, Paula N.; Ratain, Mark J.; McLeod, Howard L.; Rugo, Hope S.; Shulman, Lawrence N.; Kubo, Michiaki; Owzar, Kouros; Kroetz, Deanna L.; Medical and Molecular Genetics, School of Medicine
    Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 – 0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 – 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
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    Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients
    (American Society of Clinical Oncology, 2010-03-10) Kiyotani, Kazuma; Mushiroda, Taisei; Imamura, Chiyo K.; Hosono, Naoya; Tsunoda, Tatsuhiko; Kubo, Michiaki; Tanigawara, Yusuke; Flockhart, David A.; Desta, Zeruesenay; Skaar, Todd C.; Aki, Fuminori; Hirata, Koichi; Takatsuka, Yuichi; Okazaki, Minoru; Ohsumi, Shozo; Yamakawa, Takashi; Sasa, Mitsunori; Nakamura, Yusuke; Zembutsu, Hitoshi; Department of Medicine, IU School of Medicine
    Purpose The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods We studied 282 patients with hormone receptor–positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.
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    Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
    (American Association for Cancer Research, 2017-07-01) Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert D.; Perez-Cervantes, Carlos; El Charif, Omar; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence; Cox, Nancy J.; Dolan, M. Eileen; Travis, Lois B.; Medicine, School of Medicine
    Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.