Dataset Information

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

ABSTRACT:

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 = 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 phenomenon than those with medium or low levels (age-adjusted OR_high/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR_high/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.

SUBMITTER: Trendowski MR

PROVIDER: S-EPMC6774840 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Trendowski Matthew R MR El-Charif Omar O Ratain Mark J MJ Monahan Patrick P Mu Zepeng Z Wheeler Heather E HE Dinh Paul C PC Feldman Darren R DR Ardeshir-Rouhani-Fard Shirin S Hamilton Robert J RJ Vaughn David J DJ Fung Chunkit C Kollmannsberger Christian C Mushiroda Taisei T Kubo Michiaki M Hannigan Robyn R Strathmann Frederick F Einhorn Lawrence H LH Fossa Sophie D SD Travis Lois B LB Dolan M Eileen ME

Clinical cancer research : an official journal of the American Association for Cancer Research 20190711 19

<h4>Purpose</h4>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.<h4>Experimental design</h4>Eligible TCS given 300 or 400 (±15) mg/m<sup>2</sup> cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude se ...[more]

PMID: 31296530

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Project description:BackgroundInterindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).MethodsTo identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.ResultsSNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).ConclusionThese results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.

Project description:PurposeCisplatin, 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 designTCS (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 genome-wide association study (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.ResultsCisplatin-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 with 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 < 0.0001) 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).ConclusionsCisIT 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.

Dataset Information

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Purpose

Experimental design

Results

Conclusions

Publications

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

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