Epigenetic age acceleration in U.S. testicular cancer survivors (TCS).

Abstract

5033 Background: Given the young age at diagnosis and effective therapies (cisplatin-based chemotherapy and/or surgical approaches), most TCS gain many decades of life. Attention has been drawn to the potential downsides of these treatment successes, including the accelerated development of age-related diseases. Previous studies have suggested that cytotoxic treatment and carcinogenesis are associated with epigenetic changes, leading to premature biological aging processes. Methods: We recruited 24 TCS managed with surgical approaches alone and 24 cisplatin-treated TCS (all also treated with surgical removal of the cancerous testis) and who had histologic/serological germ cell tumor diagnosis before 55 years, and were disease-free at routine follow up. We also included 310 cancer-free race- and age-matched (+/- 5 years) males from a normative cohort, i.e., the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We undertook genome-wide interrogation of blood DNA methylation (DNAm) using the Illumina Infinium Methylation EPIC BeadChip (EPIC array). We quantified aging using DNAm GrimAge, a validated, composite biomarker consisting of DNAm surrogate biomarkers of seven plasma proteins associated with various age-related conditions plus a DNAm surrogate of smoking pack-years. The comparison analysis was adjusted for age, race, smoking status, blood cell type proportions estimated using DNA methylation batch effect, and other laboratory-related technical factors. Results: The median chronological age of TCS was 28 years (range 19-64) with 25% smokers. Compared to their chronological age, TCS managed with surgical approaches alone had a mean GrimAge of 39.4 years (i.e., 9.2 years older, paired t-test P = 0.001), and cisplatin-treated TCS had a mean GrimAge of 45.2 years (i.e., 14.9 years older, paired t-test P < 0.001). Compared to the matched CARDIA controls, TCS managed with surgical approaches alone were on average 3.0 years epigenetically older (P = 0.093), and cisplatin-treated TCS were on average 11.2 years epigenetically older (P < 0.001), suggesting an increasing trend with treatment burden (P-trend < 0.001). Conclusions: Our data showed a faster epigenetic aging process in TCS. Consistent with previous studies, our data is in line with the hypothesis that TC cytotoxic treatment may induce premature aging. Although TCS managed with surgical approaches alone had no exposure to cytotoxic drugs, their epigenetic age may also be accelerated due to TC development and/or risk factors that contributed to it as well as post-therapy factors.