Trendowski, Matthew R.El Charif, OmarRatain, Mark J.Monahan, PatrickMu, ZepengWheeler, Heather E.Dinh, Paul C., Jr.Feldman, Darren R.Ardeshir-Rouhani-Fard, ShirinHamilton, Robert J.Vaughn, David J.Fung, ChunkitKollmannsberger, ChristianMushiroda, TaiseiKubo, MichiakiHannigan, RobynStrathmann, FrederickEinhorn, Lawrence H.Fossa, Sophie D.Travis, Lois B.Dolan, M. Eileen2020-06-222020-06-222019-10-01Trendowski, M. R., El-Charif, O., Ratain, M. J., Monahan, P., Mu, Z., Wheeler, H. E., Dinh, P. C., Jr, 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., Travis, L. B., … Dolan, M. E. (2019). Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research, 25(19), 5913–5924. https://doi.org/10.1158/1078-0432.CCR-19-0113https://hdl.handle.net/1805/23037Purpose: 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.en-USPublisher PolicySerum platinum levelsCisplatin-based chemotherapyCisplatin-related toxicitiesResidual platinum valuesGenome-wide analysisClinical analysisArticle