The genomic landscape of adolescent and young adult (AYA) malignancies using DNA and RNA-based next generation sequencing.

Abstract

e15091 Background: Survival for adolescents and young adult (AYA) cancer patients (defined as age 15-39 years by the NCI) has not improved compared to survival outcomes in pediatric and older adult patients. Several factors contribute to the outcomes disparity, including lack of access to novel treatments. Currently, only a fraction of AYA cancer patients receive advanced genomic testing. Herein, we aim to characterize the molecular landscape of AYA cancers. Methods: De-identified records of 2,706 AYA patients diagnosed with solid tumors and hematologic malignancies who received Tempus xT next-generation sequencing (NGS) were identified. The prevalence of pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs), insertions/deletions (indels), fusions, and copy number alterations were assessed to describe the somatic landscape. Tumor biomarkers, such as microsatellite instability (MSI) and tumor-mutational burden (TMB) were also analyzed. Results: The cohort consisted of 2,706 AYA patients diagnosed with: central nervous system (N = 779), breast cancer (N = 700), bone and soft tissue sarcomas (N = 226), hematologic (N = 198), and gastrointestinal (GI) (N = 803) malignancies. Among 407 high-grade gliomas (HGG WHO Grade 3 & 4), variants in TP53 167 (41%), 136 (33%) IDH1, 125 (31%) ATRX, and 48 (12%) TERT were seen. Among the 82 patients with low-grade glioma (LGG, WHO Grade 1 & 2), 42 (51%) had a variant in IDH1, 40 (49%) TP53, and 35 (43%) ATRX. Among 269 patients with HR+ HER2- breast cancer, 82 (30%) had variants in TP53, 66 (25%) PIK3CA, 46 (17%) GATA3, 43 (16%) FGFR1 and 34 (13%) in ESR1. In triple-negative breast cancers (TNBC), 95 (77%) had a variant in TP53, and 9 (7.3%) in BRCA1. In ewing sarcomas (N = 36), 28 (78%) patients had a fusion with EWSR1, with TP53, STAG2, FGFR2, and RET altered in 2 (5.6%) patients. Within osteosarcomas (N = 46), 12 (26%) patients had a variant in TP53 and 9 (20%) in RB1 . In the AML subgroup (N = 34), WT1 was altered in 5 (15%) and FLT3 in 4 (12%) cases. Finally, in the GI cohort (806), 22 (5%) cases were MSI-H. Within colorectal cancer patients (N = 446), 247 (55%) patients had a variant in TP53, 150 (34%) in KRAS, 64 (14%) in PIK3CA, and several with NRG1 (8, 1.8%) and NTRK (3, 0.7%) fusions. Conclusions: We describe the somatic landscape of common malignancies in one of the largest AYA datasets. Additional analyses will focus on how this landscape differs from non-AYA age groups.