Somatic changes in Y chromosome copy number are associated with clinical and molecular features in neuroblastoma

Introduction: Neuroblastoma survival is decreased in males, and loss of the Y chromosome (LOY) has been recently shown to affect cancer incidence, survival, and response to therapy in certain tumor types; therefore, we set out to test whether LOY is linked to clinical and molecular features in neuroblastoma. Methods: Using publicly available allele-specific copy number from next-generation sequencing of neuroblastoma (Korber et al. 2023), we identified areas of duplication or deletion in regions of the Y chromosome. Y chromosome copy number was compared to molecular and clinical variables. Results: There were 64 tumors from male patients in the cohort, of whom 15 (23.4%) had loss of the Y chromosome and 12 (18.8%) had duplication of the Y chromosome. There was a significant survival advantage in patients with duplications of the Y chromosome, while there was no difference in survival in patients with LOY compared to wild type. We also tested whether LOY is associated with specific molecular features in neuroblastoma. We found that 17q gain (p=0.01) and 11q loss (p<0.001) were strongly associated with LOY, while MYCN amplification (p=0.003) was inversely associated. We also found a significant association with Alternative Lengthening of Telomeres (p<0.001). Conclusions: Our analysis shows that there are significant associations between LOY and specific molecular mechanisms in pediatric neuroblastoma. While we did not observe an association between LOY and survival, we did detect improved survival in patients with a gain of Y. This observation may be linked to other features, such as genome doubling, and merits further analysis.