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.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Longitudinal follow-up in female Childhood Cancer Survivors: no signs of accelerated ovarian function loss.

STUDY QUESTION: Is the long-term decline of ovarian function, as reflected by a decrease in serum anti-Müllerian hormone (AMH) concentration, accelerated over time in female childhood cancer survivors (CCS) as compared to healthy women of the same age? SUMMARY ANSWER: The median decline of AMH levels in long-term female CCS is not accelerated and similar to that observed in healthy controls. WHAT IS KNOWN ALREADY: Gonadal function is compromised in female CCS treated with chemotherapy and/or radiation therapy. Ovarian function is most compromised in survivors treated with total body irradiation, abdominal or pelvic irradiation, stem cell transplantation or high doses of alkylating agents. STUDY DESIGN SIZE, DURATION: Longitudinal single-centre cohort study in 192 CCS in Rotterdam, The Netherlands, between 2001 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH levels of 192 adult female CCS were assessed, at least five years after cessation of treatment and at a follow-up visit with a median of 3.2 years (range: 2.1-6.0) later and were compared to the age-based P50 of AMH in healthy controls. MAIN RESULTS AND THE ROLE OF CHANCE: Median AMH levels were below the P50 at both visit 1 (-0.59 µg/L) and at visit 2 (-0.22 µg/L). In women with a sustained ovarian function (AMH > 1.0 µg/L), the decline in AMH is similar to that in the normal population (difference in decline per year: -0.07 µg/L (range: -2.86 to 4.92), P  = 0.75). None of the treatment modalities was correlated with a significant acceleration of decline of AMH per year. LIMITATIONS REASONS FOR CAUTION: We selected CCS that visited our late effect outpatient clinic and who had two AMH levels available. It is conceivable that women without any apparent late effects of treatment as well as women with extreme late effects, which might be the ones with the largest impact on ovarian function, could be more likely to be lost to follow-up. However, general characteristics did not differ between the included and excluded patients. WIDER IMPLICATIONS OF THE FINDINGS: While prospective longitudinal research is required to strengthen our findings, they may help physicians to counsel female CCS about their expected reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: A.L.F.v.d.K., M.M.v.d.H.-E. and S.M.F.P. are supported by FP7-PanCare LIFE. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. The other authors have no conflicts of interest to declare.