Sleep health and quality of life in the Detroit Research on Cancer Survivors cohort.

PURPOSE: Sleep disturbances represent a modifiable target to improve quality of life and longer-term outcomes in cancer survivors. However, the association between sleep health and overall quality of life in African American cancer survivors has been poorly assessed, a population at increased risk for morbidity and mortality. METHODS: Seven hundred and eighteen Detroit Research on Cancer Survivors (ROCS) cohort participants completed a supplemental sleep survey at the time of enrollment, which included the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI). Linear and logistic regression was used to evaluate the association between sleep and mental health, while block regression models were used to estimate the contribution of clustered factors to Health-Related Quality of Life (HRQOL). RESULTS: Nearly 60% of the cohort reported symptoms indicative of poor sleep quality on the PSQI, 15% reported excessive daytime sleepiness on the ESS, and 12% reported moderate to severe insomnia on the ISI. Survivors with elevated ISI scores reported FACT-G scores that were 17 points lower than those without symptoms of insomnia (95% CI: - 13.1, - 21.2). Poor sleep health accounted for the largest proportion of variability in FACT-G scores (R2 = 0.27) and change in R2 value (0.18) when compared to comorbidities, health behaviors, cancer-related factors, and demographics. CONCLUSIONS: Overall sleep health was significantly associated with poorer HRQOL and variability in FACT-G scores. Additional studies investigating a causal relationship between sleep and HRQOL are needed to determine whether sleep quality could affect disparities in cancer outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Addressing sleep quality in cancer survivors may improve long-term health and HRQOL.

Assessing a Polygenic Risk Score for Lung Cancer Susceptibility in Non-Hispanic White and Black Populations.

BACKGROUND: Polygenic risk scores (PRS) have become an increasingly popular approach to evaluate cancer susceptibility, but have not adequately represented Black populations in model development. METHODS: We used a previously published lung cancer PRS on the basis of 80 SNPs associated with lung cancer risk in the OncoArray cohort and validated in UK Biobank. The PRS was evaluated for association with lung cancer risk adjusting for age, sex, total pack-years, family history of lung cancer, history of chronic obstructive pulmonary disease, and the top five principal components for genetic ancestry. RESULTS: Among the 80 PRS SNPs included in the score, 14 were significantly associated with lung cancer risk (P < 0.05) in INHALE White participants, while there were no significant SNPs among INHALE Black participants. After adjusting for covariates, the PRS was significantly associated with risk in Whites (continuous score P = 0.007), but not in Blacks (continuous score P = 0.88). The PRS remained a statistically significant predictor of lung cancer risk in Whites ineligible for lung cancer screening under current U.S. Preventive Services Task Force guidelines (P = 0.02). CONCLUSIONS: Using a previously validated PRS, we did find some predictive ability for lung cancer in INHALE White participants beyond traditional risk factors. However, this effect was not observed in Black participants, indicating the need to develop and validate ancestry-specific lung cancer risk models. IMPACT: While a previously published lung cancer PRS was able to stratify White participants into different levels of risk, the model was not predictive in Blacks. Our findings highlight the need to develop and validate ancestry-specific lung cancer risk models.

Comprehensive association analysis of speech recognition thresholds after cisplatin-based chemotherapy in survivors of adult-onset cancer.

PURPOSE: Deficits 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. METHODS: SRT 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. RESULTS: SHD 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). CONCLUSION: Current 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.

Evaluation of health behaviors and overall quality of life in younger adult African American cancer survivors.

BACKGROUND: Epidemiological studies of cancer survivors have predominantly focused on non-Hispanic White, elderly patients, despite the observation that African Americans have higher rates of mortality. Therefore, we characterized cancer survivorship in younger African American survivors using the Detroit Research on Cancer Survivors (ROCS) study to assess health behaviors and quality of life. METHODS: Five hundred and seventeen patients diagnosed with any cancer between the ages of 20-49 (mean age: 42 years; SD: 6.7 years) completed a survey to identify important clinical, behavioral, and sociodemographic characteristics, measures of health literacy, and experiences of discrimination. Quality of life outcomes were evaluated in patients using FACT-G, FACT-Cog, and PROMIS® Anxiety and Depression scales. Stepwise linear and logistic regression were used to assess the association between quality of life measures and participant characteristics. RESULTS: The mean FACT-G score was 74.1 (SD: 21.3), while the FACT-Cog was 55.1 (SD: 17.1) (FACT-G range 0-108 with higher scores indicating better function; elderly cancer patient mean: 82.2; FACT-Cog 18-item range 0-72 points with higher scores indicating better perceived cognitive functioning; scores <54 indicating cognitive impairment). In addition, 27.1% and 21.6% of patients had a score indicative of moderate or severe anxiety and depression, respectively. Perceived discrimination and the number of discriminatory events were significantly associated with reductions in three of the four quality of life measures. Health literacy was positively associated with all four health measures, while total comorbidity count was negatively associated with three of the four measures. CONCLUSION: Younger adult African American cancer survivors who report experiencing discrimination and suffer from multiple comorbid conditions have poorer mental and overall health. Understanding the unique clinical and socioeconomic stressors that influence this patient population is essential for reducing health disparities and improving long-term survivorship.

Germline Variants in DNA Damage Repair Genes and HOXB13 Among Black Patients With Early-Onset Prostate Cancer.

PURPOSE: Genetic studies of prostate cancer susceptibility have predominantly focused on non-Hispanic White men, despite the observation that Black men are more likely to develop prostate cancer and die from the disease. Therefore, we sought to identify genetic variants in Black patients diagnosed with early-onset prostate cancer. METHODS: Whole-exome sequencing of germline DNA from a population-based cohort of Black men diagnosed with prostate cancer at age 62 years or younger was performed. Analysis was focused on a panel of DNA damage repair (DDR) genes and HOXB13. All discovered variants were ranked according to their pathogenic potential based upon REVEL score, evidence from existing literature, and prevalence in the cohort. Logistic regression was used to investigate associations between mutation status and relevant clinical characteristics. RESULTS: Among 743 Black prostate cancer patients, we identified 26 unique pathogenic (P) or likely pathogenic (LP) variants in 14 genes (including HOXB13, BRCA1/2, BRIP1, ATM, CHEK2, and PALB2) among 30 men, or approximately 4.0% of the patient population. We also identified 33 unique variants of unknown significance in 16 genes among 39 men. Because of the rarity of these variants in the population, most associations between clinical characteristics did not achieve statistical significance. However, our results suggest that carriers for P or LP (P/LP) variants were more likely to have a first-degree relative diagnosed with DDR gene-associated cancer, have a higher prostate-specific antigen at time of diagnosis, and be diagnosed with metastatic disease. CONCLUSION: Variants in DDR genes and HOXB13 may be important cancer risk factors for Black men diagnosed with early-onset prostate cancer, and are more frequently observed in men with a family history of cancer.

Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy.

PURPOSE: Cisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy. METHODS: Utilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype. RESULTS: Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10-6 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10-6 ), encoding a signaling protein important in germ cell tumors. CONCLUSIONS: Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

Chemotherapy-induced peripheral neuropathy in African American cancer survivors: Risk factors and quality of life outcomes.

BACKGROUND: Epidemiological studies of chemotherapy-induced peripheral neuropathy (CIPN) have predominantly focused on non-Hispanic White patients, despite the observation that African Americans are more likely to experience CIPN. To address this health disparities gap, we sought to identify non-genetic risk factors and comorbidities associated with CIPN in African American cancer survivors using the Detroit Research on Cancer Survivors study. METHODS: Logistic regression was used to evaluate relationships between presence of self-reported CIPN and relevant clinical characteristics in 1045 chemotherapy-treated African American cancer survivors. Linear regression was used to evaluate risk factors for CIPN and quality of life outcomes that reflect physical, social, emotional, and functional domains of health. RESULTS: Patients with CIPN were more likely to report hypertension (OR = 1.28, 95% CI: 0.98-1.67, p = 0.07), hypercholesterolemia (OR = 1.32, 95% CI: 1.001-1.73, p = 0.05), history of depression (OR = 1.62, 95% CI: 1.18-2.25, p = 0.003), and diabetes (OR = 1.33, 95% CI: 0.98-1.82, p = 0.06) after adjustment for age at diagnosis, sex, and cancer site. BMI (OR = 1.02 kg/m2 , 95% CI: 1.006-1.04 kg/m2 , p = 0.008) was also positively associated with CIPN. In addition, CIPN status was significantly associated with quality of life (FACT-G total: ß = -8.60, 95% CI: -10.88, -6.32) p < 0.0001) and mood (PROMIS® Anxiety: ß = 4.18, 95% CI: 2.92-5.45, p < 0.0001; PROMIS® Depression: ß = 2.69, 95% CI: 1.53-3.84, p < 0.0001) after adjustment for age at diagnosis, sex, cancer site, and comorbidities. Neither alcohol consumption (OR = 0.88, 95% CI: 0.68-1.14, p = 0.32) nor tobacco use (ever smoked: OR = 1.04, 95% CI: 0.80-1.35, p = 0.76; currently smoke: OR = 1.28, 95% CI: 0.90-1.82, p = 0.18) was associated with increased CIPN risk. CONCLUSION: Risk factor profiles in African Americans are not entirely consistent with those previously reported for non-Hispanic White patients. Neglecting to understand the correlates of common chemotherapy-induced toxicities for this patient population may further contribute to the health disparities these individuals face in receiving adequate healthcare.

Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

BACKGROUND: Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT. METHODS: Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT-treated survivors in the Childhood Cancer Survivor Study. Genome-wide association studies (GWASs) of CRT-related tinnitus and hearing loss were also performed. RESULTS: Males were more likely to report CRT-related tinnitus (9.4% vs 5.4%; P = 5.1 × 10-4 ) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10-16 ; hearing loss: P = 6.4 × 10-9 ), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10-6 ; hearing loss: P = 1.7 × 10-6 ) in comparison with controls. GWAS of CRT-related tinnitus revealed a genome-wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10-9 ), whereas GWAS of CRT-related hearing loss identified rs332013 (P = 5.8 × 10-7 ) in chromosome 8 and rs67522722 (P = 7.8 × 10-7 ) in chromosome 6 as nearly genome-wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT-related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10-4 ). CONCLUSIONS: CRT-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use, and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722, which was supported in an independent cohort of survivors. LAY SUMMARY: Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long-term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.

Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors.

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.

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

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 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.

Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.

PURPOSE: Cisplatin, 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 DESIGN: TCS (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. RESULTS: Cisplatin-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). CONCLUSIONS: CisIT 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.

Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities.

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma.

Pemetrexed is indicated for non-small cell lung carcinoma and mesothelioma, but often has limited efficacy due to drug resistance. To probe the molecular mechanisms underlying chemotherapeutic response, we performed mRNA and microRNA (miRNA) expression profiling of pemetrexed treated and untreated lymphoblastoid cell lines (LCLs) and applied a hierarchical Bayesian method. We identified genetic variation associated with gene expression in human lung tissue for the most significant differentially expressed genes (Benjamini-Hochberg [BH] adjusted p < 0.05) using the Genotype-Tissue Expression data and found evidence for their clinical relevance using integrated molecular profiling and lung adenocarcinoma survival data from The Cancer Genome Atlas project. We identified 39 miRNAs with significant differential expression (BH adjusted p < 0.05) in LCLs. We developed a gene expression based imputation model of drug sensitivity, quantified its prediction performance, and found a significant correlation of the imputed phenotype generated from expression data with survival time in lung adenocarcinoma patients. Differentially expressed genes (MTHFD2 and SUFU) that are putative targets of differentially expressed miRNAs also showed differential perturbation in A549 fusion lung tumor cells with further replication in A549 cells. Our study suggests pemetrexed may be used in combination with agents that target miRNAs to increase its cytotoxicity.

A p53-regulated apoptotic gene signature predicts treatment response and outcome in pediatric acute lymphoblastic leukemia.

Gene signatures have been associated with outcome in pediatric acute lymphoblastic leukemia (ALL) and other malignancies. However, determining the molecular drivers of these expression changes remains challenging. In ALL blasts, the p53 tumor suppressor is the primary regulator of the apoptotic response to genotoxic chemotherapy, which is predictive of outcome. Consequently, we hypothesized that the normal p53-regulated apoptotic response to DNA damage would be altered in ALL and that this alteration would influence drug response and treatment outcome. To test this, we first used global expression profiling in related human B-lineage lymphoblastoid cell lines with either wild type or mutant TP53 to characterize the normal p53-mediated transcriptional response to ionizing radiation (IR) and identified 747 p53-regulated apoptotic target genes. We then sorted these genes into six temporal expression clusters (TECs) based upon differences over time in their IR-induced p53-regulated gene expression patterns, and found that one cluster (TEC1) was associated with multidrug resistance in leukemic blasts in one cohort of children with ALL and was an independent predictor of survival in two others. Therefore, by investigating p53-mediated apoptosis in vitro, we identified a gene signature significantly associated with drug resistance and treatment outcome in ALL. These results suggest that intersecting pathway-derived and clinically derived expression data may be a powerful method to discover driver gene signatures with functional and clinical implications in pediatric ALL and perhaps other cancers as well.