TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment

Genetic determinants of ototoxicity during and after childhood cancer treatment: Protocol for the pancarelife study

Background: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. Objective: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity. Methods: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. Results: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. Conclusions: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies

Late Effects in Childhood Cancer Survivors: Early Studies, Survivor Cohorts, and Significant Contributions to the Field of Late Effects.

With improvement in cure of childhood cancer came the responsibility to investigate the long-term morbidity and mortality associated with the treatments accountable for this increase in survival. Several large cohorts of childhood cancer survivors have been established throughout Europe and North America to facilitate research on long-term complications of cancer treatment. The cohorts have made significant contributions to the understanding of early mortality, somatic late complications, and psychosocial outcomes among childhood cancer survivors, which has been translated into the design of new treatment protocols for pediatric cancers, with the goal to reduce the potential risk and severity of late effects

Late Effects in Childhood Cancer Survivors: Early Studies, Survivor Cohorts, and Significant Contributions to the Field of Late Effects

International audienceWith improvement in cure of childhood cancer came the responsibility to investigate the long-term morbidity and mortality associated with the treatments accountable for this increase in survival. Several large cohorts of childhood cancer survivors have been established throughout Europe and North America to facilitate research on long-term complications of cancer treatment. Th

Socioeconomic characteristics and relapse-free and overall survival from childhood cancer – a nationwide study based on data from the Danish Childhood Cancer Registry

Background and purpose: Over the past decades, childhood cancer survival has increased substantially in Europe, including Denmark. However, families with fewer social resources may have benefitted less from these improvements. In this nationwide register-based study, we assessed associations between parental socioeconomic position (SEP) and 5-year relapse-free survival (RFS) and overall survival (OS) in childhood cancer patients.Material and methods: All children aged &lt;16 years diagnosed with cancer in Denmark between 1998 and 2017 were identified in the Danish Childhood Cancer Registry (N = 3245). Parents, with whom the children resided, were identified, and data on the parents’ education, cohabitation status, affiliation to work market, country of origin, and vital status of the children were obtained through individual-level linkage across Danish nationwide registries. Cox proportional hazards models were used to estimate the association between SEP indicators and 5-year RFS and OS.Results and interpretation: Tendencies towards lower 5-year RFS and OS were observed among children whose parents were unemployed/not in workforce (RFS: HR [hazard ratio] = 1.14, 95% CI [confidence interval]: 0.90–1.45, OS: HR = 1.28, 95% CI: 0.95–1.71) or from non-Western countries (RFS: HR = 1.21 95% CI: 0.96–1.52, OS: HR = 1.44, 95% CI: 1.09–1.90). Results by diagnostic groups revealed particularly low OS for children with non-central nervous system tumors whose parents were from non-Western countries (HR = 1.92, 95% CI: 1.24–2.97). Targeted strategies are needed to promote social equity and ensure optimal diagnosis, care, and management of childhood cancer across social groups.Background and purpose: Over the past decades, childhood cancer survival has increased substantially in Europe, including Denmark. However, families with fewer social resources may have benefitted less from these improvements. In this nationwide register-based study, we assessed associations between parental socioeconomic position (SEP) and 5-year relapse-free survival (RFS) and overall survival (OS) in childhood cancer patients. Material and methods: All children aged &lt;16 years diagnosed with cancer in Denmark between 1998 and 2017 were identified in the Danish Childhood Cancer Registry (N = 3245). Parents, with whom the children resided, were identified, and data on the parents’ education, cohabitation status, affiliation to work market, country of origin, and vital status of the children were obtained through individual-level linkage across Danish nationwide registries. Cox proportional hazards models were used to estimate the association between SEP indicators and 5-year RFS and OS. Results and interpretation: Tendencies towards lower 5-year RFS and OS were observed among children whose parents were unemployed/not in workforce (RFS: HR [hazard ratio] = 1.14, 95% CI [confidence interval]: 0.90–1.45, OS: HR = 1.28, 95% CI: 0.95–1.71) or from non-Western countries (RFS: HR = 1.21 95% CI: 0.96–1.52, OS: HR = 1.44, 95% CI: 1.09–1.90). Results by diagnostic groups revealed particularly low OS for children with non-central nervous system tumors whose parents were from non-Western countries (HR = 1.92, 95% CI: 1.24–2.97). Targeted strategies are needed to promote social equity and ensure optimal diagnosis, care, and management of childhood cancer across social groups.</p

Platin treatment and hearing loss: initial audiological results from PanCareLIFE

Background: Cisplatin and carboplatin are widely used in paediatric cancer treatment. Cisplatin especially can have long-term side effects, including sensorineural hearing loss. The aim of this study is to define the risk factors for platin-related ototoxicity.Materials and Methods: As part of the PanCareLIFE consortium, we gathered audiological data from 13 pan-European clinics. Eligible patients were 20 dB HL at any frequency).A total of 2,696 patients with 10,320 audiograms from various stages of cancer treatment were obtained. Audiometric data were quality-checked and classified (Münster and SIOP classifications) and 736 patients with sufficient data were phenotyped. A logistic regression investigated the likelihood of developing a hearing loss >=Münster 2b (thresholds >40 dB HL at >=4 kHz) after treatment given age, gender, cisplatin dose and cranial irradiation.Results: 48.2% of 1,385 patients with a post-treatment audiogram had clinically-relevant hearing loss (defined as >=Münster 2b) after platin treatment.Children 15 years (odds ratio 2.7, 95% CI 1.5-4.9, p=0.0006). Patients with a cumulative cisplatin dose >450 mg/m2 were more likely to develop hearing loss than those treated with carboplatin alone (OR 12.5, 95% CI 6.8-23.0, p=3.7x10-16). Treatment with cranial irradiation was more likely to lead to hearing loss than without (OR 4.5, 95% CI 3.0-6.7, p=7.2x10-13).Discussion: This is the first study of platin ototoxicity with such a large sample size. The results support tendencies found in previous studies with smaller groups. The high risk groups identified here must be monitored regularly for ototoxicity. Further detailed analyses into audiological changes and possible pharmacogenetic confounders are planned.Conclusion: 48% of patients treated with cisplatin develop clinically-relevant hearing loss. Age <5 years old, higher cumulative cisplatin doses and cranial irradiation present especially high risks.Acknowledgement: This work was supported by the PanCareLIFE consortium that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030