Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus and peripheral sensory neuropathy.
Bibliographic record
Abstract
12004 Background: Cisplatin is an essential component of first-line chemotherapy for many cancers, but causes neurotoxicity, including hearing loss (CisHL), tinnitus (CisTinn), and peripheral sensory neuropathy (CisPNeuro). However, few opportunities exist to identify risk factors and comorbidities for cisplatin-induced neurotoxicities among large numbers of homogenously treated patients without the confounding effect of cranial radiotherapy. Methods: Within a well-characterized clinical cohort of 1,680 cisplatin-treated testicular cancer survivors, linear and logistic regression analysis were utilized to analyze associations of CisHL (n = 1,258), CisTinn (n = 1,217), and CisPNeuro (n = 1,653) with non-genetic risk factors. Genome-wide association studies and gene-based analysis were performed on each phenotype. Results: Cisplatin-induced neurotoxicities (CisHL CisTinn, CisPNeuro), adjusting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension (CisTinn: OR = 2.62, p < 0.0001; CisHL: β = 0.25, p = 8.5 x10-4; CisPNeuro: OR = 1.86, p < 0.0001) and were more likely to report their health as poor (CisTinn: OR = 0.54, p < 0.0001; CisHL: β = -0.11, p < 0.0001; CisPNeuro: OR = 0.61, p < 0.0001). Persistent vertigo was significantly associated with both CisTinn (OR = 7.18, p < 0.0001) and CisPNeuro (OR = 4.29, p < 0.0001). In addition, CisTinn was significantly associated with hypercholesterolemia (OR = 1.78, p = 0.01). Importantly, gene-based association analyses identified significant associations between CisTinn and WNT8A (n = 1,037, p = 2.52x10-6) , encoding a signaling protein important in germ cell tumors; and marginal significance between CisHL and TXNRD1 (n = 1,071, p = 4.21x10-6) , thioredoxin reductase-1, which plays a key role in redox regulation. In silico analysis showed high expression levels of TXNRD1 were significantly correlated with cellular resistance to cisplatin in central nervous system tumor cells (Spearman Rho = 0.35, p = 0.04; R2= 0.14, p = 0.03), indicating TXNRD1 is protective for cisplatin-induced cytotoxicity. Previously, rs62283056 in WFS1 found to be significantly associated with CisHL (n = 511; subset of current population), was marginally significant in an independent replication cohort (p = 0.06; n = 606; subset of current population). Conclusions: Cisplatin-induced neurotoxicities are significantly associated with multiple clinical characteristics, including hypertension and self-reported poor health. WNT8A and TXNRD1 are notable risk factors for CisTinn and CisHL, respectively . Future studies should further investigate these genes and their potential impact on chemotherapy strategies. This study, based on the largest number of testicular cancer survivors investigated to date, highlights the clinical importance of these iatrogenic toxicities and their associated risk factors.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".