Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy

Matthew R. Trendowski, Omar El-Charif, Mark J. Ratain, Patrick Monahan, Zepeng Mu, Heather E. Wheeler, Paul C. Dinh, Darren R. Feldman, Shirin Ardeshir-Rouhani-Fard, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Christian Kollmannsberger, Taisei Mushiroda, Michiaki Kubo, Robyn Hannigan, Frederick Strathmann, Lawrence H. Einhorn, Sophie D. Fossa, Lois B. TravisM. Eileen Dolan

研究成果: Article

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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 biexponential 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 ¼ 2.13 103). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P ¼ 6.58 103). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P ¼ 4.6 108, 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.

元の言語English
ページ(範囲)5913-5924
ページ数12
ジャーナルClinical Cancer Research
25
発行部数19
DOI
出版物ステータスPublished - 01-10-2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Trendowski, M. R., El-Charif, O., Ratain, M. J., Monahan, P., Mu, Z., Wheeler, H. E., Dinh, P. C., Feldman, D. R., Ardeshir-Rouhani-Fard, S., Hamilton, R. J., Vaughn, D. J., Fung, C., Kollmannsberger, C., Mushiroda, T., Kubo, M., Hannigan, R., Strathmann, F., Einhorn, L. H., Fossa, S. D., ... Eileen Dolan, M. (2019). Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. Clinical Cancer Research, 25(19), 5913-5924. https://doi.org/10.1158/1078-0432.CCR-19-0113