Somatic and immune profiling of chemotherapy-associated aplastic anemia: a comparison with primary aplastic anemia and cancer without aplastic anemia

This study aimed to characterize the somatic variant candidate gene profile of patients with chemotherapy-associated aplastic anemia (CAA) and compare it with that of patients with cancer without aplastic anemia (non-AA) and primary aplastic anemia (PAA). This study included 24 patients with CAA diagnosed at Peking Union Medical College Hospital from September 2019 to May 2023 (male-to-female ratio of 3∶5; median age, 60 years). Peripheral blood samples were collected for whole-exome sequencing, and the results were compared with publicly available data of patients with non-AA and PAA. A total of 37 111 variants across 9 958 genes were detected. KEGG enrichment analysis revealed that these genes were mainly concentrated in the JAK-STAT and calcium signaling pathways (all P<0.01). Regarding human leukocyte antigen (HLA) genes, the mutation frequency of HLA-DRB1 was higher in patients with CAA than in those with non-AA cancer [false discovery rate (FDR) =0.029], whereas the mutation frequencies of HLA-A (FDR=0.082) and HLA-C (FDR=0.058) were lower than in those with PAA. For myeloid disease-related genes, compared with patients with non-AA cancer, those with CAA had higher mutation frequencies in 198 genes, including BRCA2 (FDR=0.032) and ASXL1 (FDR=0.047), and lower frequencies in SAA2 (FDR=0.049), TP53 (FDR=0.045), and PIK3CA (FDR=0.049). Compared with patients with PAA, those with CAA had higher mutation frequencies in 213 genes, including BRCA2 (FDR=0.068) and ATRX (FDR=0.072), and lower frequencies in 14 genes, including ASXL1 (FDR=0.045) and DNMT3A (FDR=0.078). In conclusion, the somatic variant profile of CAA significantly differs from that of non AA cancer and PAA: its degree of immune abnormality is higher than that in non-AA cancer but milder than that in PAA; it shows a higher potential for myeloid evolution than non-AA cancer, but its transformation mechanism is more complex than that of PAA, being influenced by multiple factors including primary tumor characteristics and myeloid gene variants.