DNA copy number patterns reveal prognostic markers and elucidate mechanisms of evolution in IDH-mutant astrocytoma

Background: Current literature suggests IDH-mutant astrocytoma contains several molecular subgroups. In this study we are interested in determining the connection between different molecular subgroups with grade and/or survival. Methods: A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by WHO 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 TCGA patients. Results: The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, p < 0.001). PTEN deletion was also associated with poor OS (7.3 vs 17.4years, p < 0.001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, p < 0.001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 yrs, p = 0.01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, p = 0.007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. Conclusions: Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.