The pan-cancer whole-genome landscape of Adolescent and Young Adult solid cancers

Cancer incidence in adolescents and young adults (AYAs; 18-39 years) is rising, but how their tumors differ genomically from those of older adults (OAs) is unclear. We analyzed paired tumor-normal whole-genomes from 698 AYAs and 5,220 OAs, with subcohorts matched by cancer group to disentangle age from tumor type. AYA tumors carried fewer somatic variants yet largely shared the same genetic drivers; many apparent age differences reflected age-dependent cancer subtypes, such as IDH-mutant glioma and HPV-positive cervical cancer. Colibactin, APOBEC and homologous recombination deficiency-associated signatures were more prevalent in AYA colorectal, gynecological and breast cancers, respectively, but were not more mutagenic when present, suggesting earlier-life activity rather than AYA-specific mutagenesis. Tumor type-concordant pathogenic germline variants were enriched in AYAs (10.9% overall versus 6.6% in matched OAs; p=0.006), often with a somatic second hit. Age thus shaped AYA cancer genomes through mutational processes, subtype composition and germline predisposition, supporting comprehensive tumor-normal profiling beyond driver-focused testing.