Correlates of health-related quality of life in African Americans diagnosed with cancer: a review of survivorship studies and the Detroit research on cancer survivors cohort.

Advances in cancer screening and treatment have improved survival after a diagnosis of cancer. As the number of cancer survivors as well as their overall life-expectancy increases, investigations of health-related quality of life (HRQOL) are critical in understanding the factors that promote the optimal experience over the course of survivorship. However, there is a dearth of information on determinants of HRQOL for African American cancer survivors as the vast majority of cohorts have been conducted predominantly among non-Hispanic Whites. In this review, we provide a review of the literature related to HRQOL in cancer survivors including those in African Americans. We then present a summary of published work from the Detroit Research on Cancer Survivors (ROCS) cohort, a population-based cohort of more than 5000 African American cancer survivors. Overall, Detroit ROCS has markedly advanced our understanding of the unique factors contributing to poorer HRQOL among African Americans with cancer. This work and future studies will help inform potential interventions to improve the long-term health of this patient population.

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.

Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach.

Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.

The promise of sonodynamic therapy.

Sonodynamic therapy is a potential cancer treatment modality that has been gaining support due to its effectiveness in both in vitro and in vivo studies. The therapeutic method combines ultrasonic irradiation with drugs known as sonosensitizers that amplify its ability to inflict preferential damage on malignant cells. This is based on the idea that ultrasonic waves have the ability to exhibit profound physical and chemical changes on cellular structure. The mechanisms by which ultrasound (US) disrupts cellular functioning can be further amplified when sonosensitizers are applied. Combining multiple sonosensitizers with US to create a substantial synergistic effect could be an effective method for destroying tumorigenic growths, while decreasing the likelihood of drug resistance.

Targeting the plasma membrane of neoplastic cells through alkylation: a novel approach to cancer chemotherapy.

BACKGROUND: Although DNA-directed alkylating agents and related compounds have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of malignant cells, their clinical utility is limited by DNA repair mechanisms and immunosuppression. However, the same destructive nature of alkylation can be reciprocated at the cell surface using novel plasma membrane alkylating agents. RESULTS: Plasma membrane alkylating agents have elicited long term survival in mammalian models challenged with carcinomas, sarcomas, and leukemias. Further, a specialized group of plasma membrane alkylating agents known as tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) potentiates a substantial leukocyte influx at the administration and primary tumor site, indicative of a potent immune response. The effects of plasma membrane alkylating agents may be further potentiated through the use of another novel class of chemotherapeutic agents, known as dihydroxyacetone phosphate (DHAP) inhibitors, since many cancer types are known to rely on the DHAP pathway for lipid synthesis. CONCLUSION: Despite these compelling data, preliminary clinical trials for plasma membrane-directed agents have yet to be considered. Therefore, this review is intended for academics and clinicians to postulate a novel approach of chemotherapy; altering critical malignant cell signaling at the plasma membrane surface through alkylation, thereby inducing irreversible changes to functions needed for cell survival.

Chemotherapy with cytochalasin congeners in vitro and in vivo against murine models.

Background Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. One of the most studied microfilament-directed agents has been cytochalasin B, a mycogenic toxin known to disrupt the formation of actin polymers. Therefore, this study sought to expand on our previous work with the microfilament-directed agent, along with other less studied cytochalasin congeners. Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells. We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro. For in vivo characterization, cytochalasins B and D were administered intraperitoneally (i.p.) to Balb/c mice challenged with drug sensitive P388-S or multidrug resistant P388/ADR leukemias. Results Cytochalasin B demonstrated higher cytotoxicity against adherent lung carcinoma and melanoma cells than against suspension P388/ADR leukemia cells, as assessed by comparative effects on cell growth, and IC50 and IC80 values. Isobolographic analysis indicated that both cytochalasin B and DiHCB demonstrate considerable drug synergy with ADR against ADR-resistant P388/ADR leukemia, while cytochalasin D exhibits only additivity with ADR against the same cell line. In vivo, cytochalasins B and D substantially increased the life expectancy of mice challenged with P388/S and P388/ADR leukemias, and in some cases, produced long-term survival. Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

Chemotherapy in vivo against M109 murine lung carcinoma with cytochalasin B by localized, systemic, and liposomal administration.

Cytochalasin B is a potentially novel microfilament-directed chemotherapeutic agent that prevents actin polymerization, thereby inhibiting cytokinesis. Although cytochalasin B has been extensively studied in vitro, only limited data are available to assess its in vivo potential. Cytochalasin B was administered to Balb/c mice challenged i.d. with M109 murine lung carcinoma to determine whether the agent could affect an established i.d. tumor when the compound is administered s.c. in the region of the i.d. tumor, but not in direct contact with it. Cytochalasin B was also administered either i.p. or s.c. at a distant site or i.v. to determine whether it could affect the long-term development of an established i.d. tumor. Cytochalasin B was then liposome encapsulated to determine whether the maximum tolerated dose (MTD) of the compound could be increased, while reducing immunosuppression that we have previously characterized. Liposomal cytochalasin B was also administered to mice challenged i.d. with M109 lung carcinoma to assess its chemotherapeutic efficacy. The results can be summarized as follows: 1) cytochalasin B substantially delayed the growth of i.d. M109 tumor nodules, inhibited metastatic progression in surrounding tissues, and produced long-term cures in treated mice; 2) liposomal cytochalasin B increased the i.p. MTD by more than 3-fold, produced a different distribution in tissue concentrations, and displayed antitumor effects against M109 lung carcinoma similar to non-encapsulated cytochalasin B. These data show that cytochalasin B exploits unique chemotherapeutic mechanisms and is an effective antineoplastic agent in vivo in pre-clinical models, either in bolus form or after liposome encapsulation.

Effects of mTOR inhibitors and cytoskeletal-directed agents alone and in combination against normal and neoplastic hematopoietic cells in vitro.

The mechanistic target of rapamycin (mTOR) controls cell growth and enlargement and has been found to be aberrant in a wide variety of malignancies. Although mTOR is already an attractive antineoplastic target, overexpression or aberrant expression of mTOR may also provide an opportunity to further increase the size differential between malignant and normal cells, providing an opportunity to amplify and exploit cell size differences between neoplastic cells and their normal counterparts using physiochemical treatment modalities. Therefore, this study sought to quantify the concentration response and time course effects of rapamycin on cell cycle entry, cell enlargement, and cell proliferation in U937 human monocytic leukemia and human hematopoietic stem cells (hHSCs). In addition, the effects of combination treatment with mTOR inhibitors (rapamycin, everolimus, and temsirolimus) and cytoskeletal-directed agents (cytochalasin B and vincristine) in leukemic cells (U937, THP1, K562, Molt-4, and L1210) were assessed for potential drug synergy. While both U937 cells and hHSCs exhibited a marked reduction in cell volume, U937 cells were able to proliferate in the presence of rapamycin ranging from 0.5 nM to 10 µM (10,000 nM), whereas hHSCs were able to proliferate only at lower concentrations, and were completely inhibited from proliferation by 8 nM rapamycin. These effects were observed with as little as 0.5 nM rapamycin, demonstrating the profound affinity the compound has for FK-binding protein 12 (FKBP12), which subsequently forms the FKBP12/rapamycin complex to inhibit mTOR. Rapamycin continued to exert effects on cell size and proliferation even at 10 µM, without producing marked cytotoxicity. Although cytochalasin B and vincristine were unable to substantially enlarge rapamycin-treated leukemia cells, it appears that rapamycin and its associated analogs everolimus and temsirolimus have notable synergistic potential with microfilament-disrupting cytochalasin B and microtubule-disrupting vincristine as assessed by comparative effects on cell growth, annexin V staining, IC30 isobolograms, and Chou-Talalay statistics. These observations indicate a potentially novel therapeutic rationale for hematological malignancies and for other cancers to elicit the preferential destruction of neoplastic cells that aberrantly express mTOR.

Effects of cytochalasin congeners, microtubule-directed agents, and doxorubicin alone or in combination against human ovarian carcinoma cell lines in vitro.

BACKGROUND: Although the actin cytoskeleton is vital for carcinogenesis and subsequent pathology, no microfilament-directed agent has been approved for cancer chemotherapy. One of the most studied classes of microfilament-directed agents has been the cytochalasins, mycotoxins known to disrupt the formation of actin polymers. In the present study, we sought to determine the effects of cytochalasin congeners toward human drug sensitive and multidrug resistant cell lines. METHODS: SKOV3 human ovarian carcinoma and several multidrug resistant derivatives were tested for sensitivity against a panel of nine cytochalasin congeners, as well as three clinically approved chemotherapeutic agents (doxorubicin, paclitaxel, and vinblastine). In addition, verapamil, a calcium ion channel blocker known to reverse P-glycoprotein (P-gp) mediated drug resistance, was used in combination with multiple cytochalasin congeners to determine whether drug sensitivity could be increased. RESULTS: While multidrug resistant SKVLB1 had increased drug tolerance (was more resistant) to most cytochalasin congeners in comparison to drug sensitive SKOV3, the level of resistance was 10 to 1000-fold less for the cytochalasins than for any of the clinically approved agents. While cytochalasins did not appear to alter the expression of ATP binding cassette (ABC) transporters, several cytochalasins appeared to inhibit the activity of ABC transporter-mediated efflux of rhodamine 123 (Rh123), suggesting that these congeners do have affinity for drug efflux pumps. Cytochalasins also appeared to significantly decrease the F/G-actin ratio in both drug sensitive and drug resistant cells, indicative of marked microfilament inhibition. The cytotoxicity of most cytochalasin congeners could be increased with the addition of verapamil, and the drug sensitivity of resistant SKVLB1 to the clinically approved antineoplastic agents could be increased with the addition of cytochalasins. As assessed by isobolographic analysis and Chou-Talalay statistics, cytochalasin B and 21,22-dihydrocytochalasin B (DiHCB) demonstrated notable synergy with doxorubicin and paclitaxel, warranting further investigation in a tumor-bearing mammalian model. CONCLUSION: Cytochalasins appear to inhibit the activity of P-gp and potentially other ABC transporters, and may have novel activity against multidrug resistant neoplastic cells that overexpress drug efflux proteins.

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction.

Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.

The rhetoric of cancer.

BACKGROUND: Research involving the discovery of novel anticancer drugs and treatments hold precedence among the general public. However, investigating the etiology and epidemiology of malignancies can have a significant effect on reducing the prevalence of cancer in society. Understanding risk factors that drive neoplastic development can provide educated individuals the opportunity to avoid such catalysts. METHODS: Literature searches were conducted on prominent magazine and newspaper sources to analyze the accuracy and relevance the material had toward cancer prevention. Additionally, two professionals involved in oncology were interviewed to gain a more personal view of the population's knowledge on cancer awareness and prevention. RESULTS: The lack of attention paid to the understanding of cancer and its subsequent prevention has resulted in fundamental misconceptions that facilitate the development of neoplastic growths. CONCLUSIONS: Addressing the lack of attention paid to cancer awareness and prevention through proper education can have a significant effect on limiting the impact cancer has on society.

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.

Evaluation of the Immune Response within the Tumor Microenvironment in African American and Non-Hispanic White Patients with Non-Small Cell Lung Cancer.

BACKGROUND: African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in immune response have been minimal. Therefore, we compared components of the tumor microenvironment among African Americans and non-Hispanic Whites diagnosed with non-small cell lung cancer based on PDL1 or tertiary lymphoid structure (TLS) status to identify differences of translational relevance. METHODS: Using a cohort of 280 patients with non-small cell lung cancer from the Inflammation, Health, Ancestry, and Lung Epidemiology study (non-Hispanic White: n = 155; African American: n = 125), we evaluated PDL1 tumor proportion score (<1% vs. ≥1%) and TLS status (presence/absence), comparing differences within the tumor microenvironment based on immune cell distribution and differential expression of genes. RESULTS: Tumors from African Americans had a higher proportion of plasma cell signatures within the tumor microenvironment than non-Hispanic Whites. In addition, gene expression patterns in African American PDL1-positive samples suggest that these tumors contained greater numbers of γδ T cells and resting dendritic cells, along with fewer CD8+ T cells after adjusting for age, sex, pack-years, stage, and histology. Investigation of differential expression of B cell/plasma cell-related genes between the two patient populations revealed that two immunoglobulin genes (IGKV2-29 and IGLL5) were associated with decreased mortality risk in African Americans. CONCLUSIONS: In the first known race-stratified analysis of tumor microenvironment components in lung cancer based on PDL1 expression or TLS status, differences within the immune cell composition and transcriptomic signature were identified that may have therapeutic implications. IMPACT: Future investigation of racial variation within the tumor microenvironment may help direct the use of immunotherapy.

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.

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.

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.

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 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.