Importance Cisplatin is highly ototoxic but widely used. Evidence is lacking regarding cisplatin-related hearing loss (CRHL) in adult-onset cancer survivors with comprehensive audiologic assessments (eg, Words-in-Noise [WIN] tests, full-spectrum audiometry, and additional otologic measures), as well as the progression of CRHL considering comorbidities, modifiable factors associated with risk, and cumulative cisplatin dose. Objective To assess CRHL with comprehensive audiologic assessments, including the WIN, evaluate the longitudinal progression of CRHL, and identify factors associated with risk. Design, Setting, and Participants The Platinum Study is a longitudinal study of cisplatin-treated testicular cancer survivors (TCS) enrolled from 2012 to 2018 with follow-up ongoing. Longitudinal comprehensive audiologic assessments at Indiana University and Memorial Sloan Kettering Cancer Center included 100 participants without audiometrically defined profound hearing loss (HL) at baseline and at least 3.5 years from their first audiologic assessment. Data were analyzed from December 2013 to December 2022. Exposures Factors associated with risk included cumulative cisplatin dose, hypertension, hypercholesterolemia, diabetes, tobacco use, physical inactivity, body mass index, family history of HL, cognitive dysfunction, psychosocial symptoms, and tinnitus. Main Outcomes and Measures Main outcomes were audiometrically measured HL defined as combined-ears high-frequency pure-tone average (4-12 kHz) and speech-recognition in noise performance measured with WIN. Multivariable analyses evaluated factors associated with risk for WIN scores and progression of audiometrically defined HL. Results Median (range) age of 100 participants at evaluation was 48 (25-67) years; median (range) time since chemotherapy: 14 (4-31) years. At follow-up, 78 (78%) TCS had audiometrically defined HL; those self-reporting HL had 2-fold worse hearing than TCS without self-reported HL (48 vs 24 dB HL; P < .001). A total of 54 (54%) patients with self-reported HL showed clinically significant functional impairment on WIN testing. Poorer WIN performance was associated with hypercholesterolemia (beta = 0.88; 95% CI, 0.08 to 1.69; P = .03), lower-education (F1 = 5.95; P = .004), and severity of audiometrically defined HL (beta = 0.07; 95% CI, 0.06 to 0.09; P < .001). CRHL progression was associated with hypercholesterolemia (beta = -4.38; 95% CI, -7.42 to -1.34; P = .01) and increasing age (beta = 0.33; 95% CI, 0.15 to 0.50; P < .001). Importantly, relative to age-matched male normative data, audiometrically defined CRHL progression significantly interacted with cumulative cisplatin dose (F1 = 5.98; P = .02); patients given 300 mg/m2 or less experienced significantly less progression, whereas greater temporal progression followed doses greater than 300 mg/m(2). Conclusions and Relevance Follow-up of cisplatin-treated cancer survivors should include strict hypercholesterolemia control and regular audiological assessments. Risk stratification through validated instruments should include querying hearing concerns. CRHL progression relative to age-matched norms is likely associated with cumulative cisplatin dose; investigation over longer follow-up is warranted.

Abstract Background: Studies have shown that taxane-treated breast cancer patients with African (AFR) ancestry experience worse peripheral sensory neuropathy (PSN), while African American vincristine-treated leukemia patients have less PSN than Europeans (EUR). We hypothesized that ancestral disparities may exist for cisplatin-induced neurotoxicities and may relate to differences in allele frequency and resultant gene expression of SNPs associated with these toxicities. Methods: In our Platinum Study of 1680 genotyped testicular cancer survivors (TCS), multidimensional scaling scores were anchored by the 1000 Genomes population to classify geographic ancestry. PSN (EORTC-CIPN20) and other toxicities plus clinical and lifestyle variables were examined for associations between geographic ancestry and phenotypes using logistic regression and Wilcoxon rank sum test. Genotyped SNPs with Fst > 0.25 in 1000 Genomes were identified and evaluated with GTEx data to find expression or splicing quantitative trait loci in nerve/brain tissue or for cisplatin-associated candidate genes, across all tissues. LDmatrix was used to find linkage disequilibrium. If a block of SNPs had R2 > 0.75, one independent SNP was kept for association analysis. Logistic regression with age at questionnaire completion and 10 genetic principal components as covariates was used to calculate the association between genotype and toxicity. Results: In an analysis of patients who received 400-450 mg/m2 of cisplatin including EUR (n=681), Asian (ASN) axis (n=44) and AFR (n=13), the odds ratio (OR) for any neuropathy vs. none in the AFR vs. EUR was 7.8 (P=0.049) and in the AFR vs. ASN axis (including East Asian 1000 Genomes populations) was 10.0 (P=0.034). TCS with AFR ancestry had significantly more vertigo. There were 19,874 SNPs for analysis from the genome-wide approach and 118 SNPs from the candidate gene approach. While associations between genotype and toxicity did not reach Bonferroni threshold, some SNPs had p-values in the 10-5 range. For PSN, one SNP had increased frequency of a risk allele in the AFR population while the other had increased frequency of a protective allele, while for vertigo, four SNPs had increased frequency of risk alleles in the AFR population. Of interest was rs34904346, in which the TT vs. AA genotype had an OR of 1.9 (p=2x10-5) for any vs. no PSN, with the T allele having 90% frequency in AFR ancestry patients versus ∼60% in other populations. This SNP and three other independent SNPs associated with PSN incidence (p∼10-3) are eQTLs for RNF24 in nerve tissue, which interacts with membrane proteins that regulate intracellular calcium levels. Conclusions: We show preliminary evidence for the role of differing risk allele frequencies across populations in explaining disparities in cisplatin-induced PSN and vertigo, likely in combination with structural and environmental factors. Genotyping risk alleles could customize dosing, treatment, and post-treatment monitoring to benefit all cisplatin-treated patients. Citation Format: Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, Chunkit Fung, David J. Vaughn, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, Eileen Dolan. Impact of population pharmacogenomics on cisplatin-induced neurotoxicities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C051.

BACKGROUND:No study has quantified the impact of pain and other adverse health outcomes on global physical and mental health in long-term US testicular cancer survivors or evaluated patient-reported functional impairment due to pain. METHODS:Testicular cancer survivors given cisplatin-based chemotherapy completed validated surveys, including Patient-Reported Outcomes Measurement Information System v1.2 global physical and mental health, Patient-Reported Outcomes Measurement Information System pain questionnaires, and others. Multivariable linear regression examined relationships between 25 adverse health outcomes with global physical and mental health and pain-interference scores. Adverse health outcomes with a β^  of more than 2 are clinically important and reported below. RESULTS:Among 358 testicular cancer survivors (median age = 46 years, interquartile range [IQR] = 38-53 years; median time since chemotherapy = 10.7 years, IQR = 7.2-16.0 years), median adverse health outcomes number was 5 (IQR = 3-7). A total of 12% testicular cancer survivors had 10 or more adverse health outcomes, and 19% reported chemotherapy-induced neuropathic pain. Increasing adverse health outcome numbers were associated with decreases in physical and mental health (P < .0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (β^ = -3.72; P = .001), diabetes (β^ = -4.41; P = .037), obesity (β^ = -2.01; P = .036), and fatigue (β^ = -8.58; P < .0001) were associated with worse global mental health, while being married or living as married benefited global mental health (β^ = 3.63; P = .0006). Risk factors for pain-related functional impairment included lower extremity location (β^ = 2.15; P = .04) and concomitant peripheral artery disease (β^ = 4.68; P < .001). Global physical health score reductions were associated with diabetes (β^ = -3.81; P = .012), balance or equilibrium problems (β^ = -3.82; P = .003), cognitive dysfunction (β^ = -4.43; P < .0001), obesity (β^ = -3.09; P < .0001), peripheral neuropathy score (β^ = -2.12; P < .0001), and depression (β^ = -3.17; P < .0001). CONCLUSIONS:Testicular cancer survivors suffer adverse health outcomes that negatively impact long-term global mental health, global physical health, and pain-related functional status. Clinically important factors associated with worse physical and mental health identify testicular cancer survivors requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional status and mental health 10 or more years after treatment.

PURPOSE Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. PATIENTS AND METHODS Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. RESULTS HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score ( P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). CONCLUSION One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

PDF file, 52KB, Oligonucleotides used for β-tubulins mRNA quantification and TUBB2A sequencing and cloning.

Purpose Ototoxicityis a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors. Methods Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher's exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. Results Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P = 0.008), and difficulty hearing (P < .001). Tinnitus was also significantly related to age at survey completion ( OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001). TC survivors with hearing loss were more likely to report diabetes (P = 0.042), hypertension ( P = 0.007), hypercholesterolemia (P < 0.001), and family history of hearing loss (P = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071). Conclusions Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. Implications for Cancer Survivors Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

AbstractPurposeDeficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin.MethodsSRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT‐based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank‐based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses.ResultsSHD was inversely associated with self‐reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p < 0.001), and peripheral motor neuropathy (p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD (p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value < 5 × 10−8, 22 genetic variants were suggestively associated (p < 10−5) with SRT deterioration. Three of the top variants in 10 respective linkage disequilibrium regions were either positioned within the coding sequence or were eQTLs for genes involved in neuronal development (ATE1, ENAH, and ZFHX3).ConclusionCurrent results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT.

OBJECTIVES:To provide new information on factors associated with discrepancies between patient-reported and audiometrically defined hearing loss (HL) in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT) and to comprehensively investigate risk factors associated with audiometrically defined HL. DESIGN:A total of 1410 testicular cancer survivors (TCS) ≥6 months post-CBCT underwent comprehensive audiometric assessments (0.25 to 12 kHz) and completed questionnaires. HL severity was defined using American Speech-Language-Hearing Association criteria. Multivariable multinomial regression identified factors associated with discrepancies between patient-reported and audiometrically defined HL and multivariable ordinal regression evaluated factors associated with the latter. RESULTS:Overall, 34.8% of TCS self-reported HL. Among TCS without tinnitus, those with audiometrically defined HL at only extended high frequencies (EHFs) (10 to 12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25 to 8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically defined HL (8.1%) [odds ratio (OR) = 2.48; 95% confidence interval (CI), 1.31 to 4.68; and OR = 3.49; 95% CI, 1.89 to 6.44, respectively]. Older age (OR = 1.09; 95% CI, 1.07 to 1.11, p < 0.0001), absence of prior noise exposure (OR = 1.40; 95% CI, 1.06 to 1.84, p = 0.02), mixed/conductive HL (OR = 2.01; 95% CI, 1.34 to 3.02, p = 0.0007), no hearing aid use (OR = 5.64; 95% CI, 1.84 to 17.32, p = 0.003), and lower education (OR = 2.12; 95% CI, 1.23 to 3.67, p = 0.007 for high school or less education versus postgraduate education) were associated with greater underestimation of audiometrically defined HL severity, while tinnitus was associated with greater overestimation (OR = 4.65; 95% CI, 2.64 to 8.20 for a little tinnitus, OR = 5.87; 95% CI, 2.65 to 13.04 for quite a bit tinnitus, and OR = 10.57; 95% CI, 4.91 to 22.79 for very much tinnitus p < 0.0001). Older age (OR = 1.13; 95% CI, 1.12 to 1.15, p < 0.0001), cumulative cisplatin dose (>300 mg/m2, OR = 1.47; 95% CI, 1.21 to 1.80, p = 0.0001), and hypertension (OR = 1.80; 95% CI, 1.28 to 2.52, p = 0.0007) were associated with greater American Speech-Language-Hearing Association-defined HL severity, whereas postgraduate education (OR = 0.58; 95% CI, 0.40 to 0.85, p = 0.005) was associated with less severe HL. CONCLUSIONS:Discrepancies between patient-reported and audiometrically defined HL after CBCT are due to several factors. For survivors who self-report HL but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments should be considered.

The National Cancer Institute's Youth Enjoy Science Research Education Program (YES) supports cancer-based research experiences, curriculum development and outreach activities to foster diversity in the biomedical workforce. The University of Chicago Medicine Comprehensive Cancer Center was among the first recipients of the YES award in 2017, launching the Chicago EYES (Educators and Youth Enjoy Science) on Cancer program for high school and college students. The EYES team also introduced immersive research experiences and mentored curriculum development for high school science teachers, a potentially powerful means to extend science enrichment and career exposure to schools across Chicago. Ongoing evaluation of the EYES program suggests positive outcomes in terms of trainees' research skill development and their knowledge about, and positive attitudes towards, careers in biomedicine. Teacher research fellows reported that the program inspired new insights about science learning and practice that not only strengthened their skills as science educators, but also improved their ability to relate to their pupils. These findings contribute to the broader effort to establish best practices among cancer research training programs, particularly those with a shared mission to empower youth from diverse backgrounds to contribute to a field deeply in need of their talents and perspectives.

e24066 Background: Cisplatin treatment is used for many cancers, including testicular, ovarian, and head and neck malignancies. Cancer survivors with multiple cisplatin-related toxicities can have poor health-related quality of life (HRQOL). Identification of clinical and genetic factors that predict the risk of these neurotoxicities is critical. Methods: Testicular cancer survivors (TCS) enrolled in the Platinum Study completed surveys, underwent physical examination, extensive audiometric testing, and phlebotomy for genotyping and serum platinum analysis. Cases included TCS with two or more severe toxicities (hearing loss [HL], tinnitus, and peripheral sensory neuropathy [PSN]), defined as follows: hearing threshold > 40dB based on geometric mean of 4-12kHz, responding yes to “Do you have ringing or buzzing in the ears?” and/or EORTC-CIPN20 scores in the severe range for items related to sensory neuropathy. Controls were restricted to TCS without any toxicities. TCS with a single toxicity were excluded from analyses. Penalized logistic regression lasso method was used to create the model to predict the binary outcome. Creatinine clearance and residual serum platinum levels were calculated. Polygenic risk scores (PRS) for traits commonly associated with pharmacokinetics and HL, tinnitus, and PSN were calculated for TCS in the training (n = 284) and validation (n = 157) data sets using PRS publicly available in The Polygenic Score Catalog using PRSice 2.3.3. Models were trained and tested in R 4.1.2. Results: A model to assess the risk of developing multiple severe neurotoxicities that could be used without blood work and additional analysis was developed. Clinical predictors incorporated into the model were age at testicular cancer diagnosis, age at phlebotomy, weight and height. PRS incorporated were age-related sensorineural hearing loss (PGS000762), body fat percentage (PGS002133), creatinine in urine (PGS001944), and peripheral nervous system disease (PGS002039). The accuracy of this model was 77.71%, which was significantly greater than the no information rate (NIR) of 65.61% (p = .00067). The positive and negative predictive values (PPV and NPV) were 72.09% and 79.82%, respectively. The AUC-ROC was 0.804. Adding residual platinum levels and creatinine clearance increased the accuracy of the model to 78.34%, which was significantly greater than the NIR (p = .00035). The PPV was 75.00% and the NPV was 79.49%. The area under the receiver operating characteristic curve (AUC-ROC) was 0.832. Conclusions: TCS are often faced with multiple severe neurotoxicities such as HL, tinnitus, and PSN, which impact HRQOL for many decades. If confirmed, a penalized regression model using clinical and genetic characteristics can predict the risk of developing these phenotypes to guide clinicians in treatment and post-treatment management plans.

Most cancer chemotherapeutic agents are ineffective in a subset of patients, thus it is important to consider the role of genetic variation in drug response. Lymphoblastoid cell lines (LCLs) in 1000 Genomes Project populations of diverse ancestries are a useful model for determining how genetic factors impact variation in cytotoxicity. In our study, LCLs from three 1000 Genomes Project populations of diverse ancestries were previously treated with increasing concentrations of eight chemotherapeutic drugs and cell growth inhibition was measured at each dose with half-maximal inhibitory concentration (IC50) or area under the dose-response curve (AUC) as our phenotype for each drug. We conducted both genome-wide (GWAS) and transcriptome-wide association studies (TWAS) within and across ancestral populations. We identified four unique loci in GWAS and three genes in TWAS significantly associated with chemotherapy-induced cytotoxicity within and across ancestral populations. For etoposide, increased STARD5 predicted expression associated with decreased etoposide IC50 (p = 8.5 x 10-8). Functional studies in A549, a lung cancer cell line, revealed that knockdown of STARD5 expression resulted in decreased sensitivity to etoposide following exposure for 72 (p = 0.033) and 96 hours (p = 0.0001). By identifying loci and genes associated with cytotoxicity across ancestral populations, we strive to understand the genetic factors impacting the effectiveness of chemotherapy drugs and to contribute to the development of future cancer treatment.

5016 Background: Although pure-tone audiometry is the gold standard to evaluate hearing loss (HL), patient-reported outcomes are practically more time and cost effective. However, no data exist on factors associated with discrepancies between patient-reported and audiometrically-defined HL in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT); and few comprehensive assessments of factors associated with audiometrically-defined HL have been conducted. Methods: A total of 1,410 testicular cancer survivors (TCS) ≥6 months post-CBCT completed comprehensive audiometric assessments (0.25-12 kHz) and detailed questionnaires of sociodemographic, clinical, and health behaviors. Audiometrically-defined HL severity was defined using American Speech-Language-Hearing Association (ASHA) criteria. Multivariable multinomial logistic regression identified factors associated with discrepancies (overestimation and underestimation vs. concordance), between patient-reported and audiometrically-defined HL and multivariable ordinal logistic regression evaluated factors associated with the HL severity. Results: Overall, 34.8% of TCS self-reported HL, while 77.8% had audiometrically-defined HL. Among TCS without tinnitus, those with audiometrically-defined HL at only extended high frequencies (EHFs) (10-12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25-8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically-defined HL (8.1%) (OR = 2.48; 95%CI, 1.31-4.68 and OR = 3.49; 95%CL,1.89-6.44, respectively). Older age (OR = 1.09; P< 0.0001), absence of prior noise exposure (OR = 1.40; P= 0.02), and mixed/conductive HL (OR = 2.01; P= 0.0007) were associated with greater underestimation of audiometrically-defined HL severity. Hearing aid use (OR = 0.18; P= 0.003) and higher education ( P= 0.004) were associated with less underestimation of audiometrically-defined HL severity, while tinnitus was associated with greater overestimation ( P< 0.0001). Older age (OR = 1.13; P< 0.0001), cumulative cisplatin dose ( > 300 mg/m 2, OR = 1.47; P= 0.0001), and hypertension (OR = 1.80; P= 0.0007) were associated with greater ASHA-defined HL severity, whereas post-graduate education (OR = 0.58; P= 0.005) was associated with less severe HL. Conclusions: Discrepancies between patient-reported and audiometrically-defined HL after CBCT are associated with several factors including age, education, tinnitus, prior noise exposure, use of hearing aids, and conductive HL. Understanding these factors will help clinicians to better interpret self-reported HL as a surrogate for audiometric assessments. For survivors who self-report HL, but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments, should be considered.

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose-limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR-induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human-induced pluripotent stem cell-derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR's antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Abstract Purpose: Cytarabine is an effective treatment for AML with associated toxicities including treatment related mortality (TRM). The purpose is to determine the clinical relevance of SNPs identified through the use of HapMap lymphoblastoid cell-based models, in predicting cytarabine response and toxicity in AML. Experimental Design: We tested clinical significance of SNPs associated with cytarabine sensitivity in children with AML treated on Children's Oncology Group regimens (CCG 2941/2961). Endpoints included overall survival (OS), event-free survival (EFS), and TRM. Patients who received bone marrow transplant were excluded. We tested 124 SNPs associated with cytarabine sensitivity in HapMap cell lines in 348 children to determine whether any associated with treatment outcomes. In addition, we tested five SNPs previously associated with TRM in children with AML in our independent dataset of 385 children. Results: Homozygous variant genotypes of rs2025501 and rs6661575 had increased in vitro cellular sensitivity to cytarabine and were associated with increased TRM. TRM was particularly increased in children with variant genotype randomized to high-dose cytarabine (rs2025501: P = 0.0024 and rs6661575 P = 0.0188). In analysis of previously reported SNPs, only the variant genotype rs17202778 C/C was significantly associated with TRM (P < 0.0001). Conclusions: We report clinical importance of two SNPs not previously associated with cytarabine toxicity. Moreover, we confirm that SNP rs17202778 significantly impacts TRM in pediatric AML. Cytarabine sensitivity genotypes may predict TRM and could be used to stratify to standard versus high-dose cytarabine regimens, warranting further study in prospective AML trials.

Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea—DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = − 0.74; P = 1.46 × 10–23), representing a previously unidentified mechanism for HFS. This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Abstract Purpose: Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities. Experimental Design: The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed. Results: Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines. Conclusions: Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

A large number of single nucleotide variants (SNVs) in the human genome are known to be responsible for inherited disease. An even larger number of SNVs, particularly those located in introns, have yet to be investigated for their pathogenic potential. Using known pathogenic and neutral intronic SNVs (iSNVs), we developed the regSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure and evolutionary conservation features. regSNPs-intron showed high accuracy in computing disease-causing probabilities of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we validated regSNPs-intron predictions by measuring the impact of iSNVs on splicing outcome. Together, regSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis. regSNPs-intron is available at https://regsnps-intron.ccbb.iupui.edu .

Single nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we evaluate the impact of RegSNPs-intron predictions on splicing outcome. Together, RegSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis.

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/m 2 (OR, 2.08; P = .011) or ≥30 kg/m 2 (OR, 2.36; P = .005) compared with <25 kg/m 2 . 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.

Peripheral neuropathy is a well recognised treatment-related toxicity in children with cancer, associated with exposure to neurotoxic chemotherapy agents. Acute damage can occur in sensory, motor, or autonomic neurons, with symptoms that are rarely life threatening, but often severe enough to interfere with function during therapy and after treatment ends. The type of neuropathy and specific symptoms are associated with multiple factors including age at time of therapy, genetic predisposition, chemotherapy type and cumulative dose, and exposure to other agents during therapy. In this Review, we describe the peripheral neuropathy phenotype in children during cancer therapy and among survivors who have completed therapy, to summarise genetic and treatment-related risk factors for neuropathy, and to outline strategies to monitor and detect neuropathy during and after therapy. Additionally, we outline strategies for medical management of neuropathy during treatment and potential rehabilitation interventions to prevent or remediate functional loss.