Abstract PR014: Male Y chromosome loss as a candidate driver in high-risk neuroblastoma

Abstract

Cancer incidence is generally biased towards male patients in both children and adults. The reasons for this discrepancy remain largely unclear, especially in children who have not had extensive exposure to environmental or occupational mutagens or sex hormones. Male and female cells are distinguished by their complement of the sex chromosomes X and Y, with males possessing XY, and females carrying XX. This raises important questions about how these intrinsic genetic differences influence tumorigenesis, progression and response to therapy. We have previously demonstrated the frequent loss of the male Y chromosome (LOY) in various cancers in adults and shown that this alteration is a likely driver in certain tumor types. Using published data from the OpenPedCan cohort, we now present a comprehensive analysis of Y chromosome somatic alterations across 20 solid and hematologic pediatric tumor types. We find that LOY is overall much rarer than in adult tumors, potentially reflecting general differences in the frequency of genetic drivers between pediatric and adult malignancies and the absence of age as a driver of somatic Y loss. In neuroblastoma, however, LOY affects 24% of male tumors of all stages, is strongly associated with age at diagnosis (318 months) and high-risk disease, where Y chromosome loss occurs in 35% of tumors. Notably, LOY predominantly occurs in tumors without amplification of MYCN, a well-established oncogene and genetic risk, suggesting that LOY represents an independent risk factor in this disease. We further show that Y loss occurs early during neuroblastoma tumor evolution and is largely clonal, suggesting a role as an early or selective driver. Our findings validate in additional tumor cohorts, demonstrating that LOY is likely a critical somatic event in this disease. In vitro cell line models with LOY have specific dependencies on X-linked homologs of genes encoded on the Y chromosome, a vulnerability that could be potentially be therapeutically exploited.