Abstract
Fusion genes (FGs) are important genetic abnormalities in acute leukemias, but their variety and occurrence in acute leukemias remain to be systematically described. Whole transcriptome sequencing (WTS) provides a powerful tool for analyzing FGs. Here we report the FG map revealed by WTS in a consecutive cohort of 1000 acute leukemia cases in a single center, including 539 acute myeloid leukemia (AML), 437 acute lymphoblastic leukemia (ALL), and 24 mixed-phenotype acute leukemia (MPAL) patients. Bioinformatic analysis identified 792 high-confidence in-frame fusion events (296 distinct fusions) which were classified into four tiers. Tier A (pathogenic), B (likely pathogenic), and C (uncertain significance) FGs were identified in 61.8% cases of the total cohort (59.7% in AML, 64.5% in ALL, and 63.6% in MPAL). FGs involving protein kinase, transcription factor, and epigenetic genes were detected in 10.7%, 48.5%, and 15.1% cases, respectively. A considerable amount of novel FGs (82 in AML, 88 in B-ALL, 13 in T-ALL, and 9 in MPAL) was identified. This comprehensively described real map of FGs in acute leukemia revealed multiple FGs with clinical relevance that have not been previously recognized. WTS is a valuable tool and should be widely used in the routine diagnostic workup of acute leukemia.
Highlights
Fusion genes (FGs) are major molecular biological abnormalities in acute leukemia, and all well-known FGs in leukemias are founder variations and play as crucial tumorigenesis factors
Ever since screening multiple common FGs simultaneously and quantitatively monitoring the positive ones have been introduced into the routine clinical diagnostic workup of acute leukemia
We have previously reported common FGs were presented in ~41% of acute myeloid leukemia (AML) and 29% of acute lymphoblastic leukemia (ALL) cases, respectively [2, 3]
Summary
Fusion genes (FGs) are major molecular biological abnormalities in acute leukemia, and all well-known FGs in leukemias are founder variations and play as crucial tumorigenesis factors. Pathogenicity evaluation of FGs We classified the final FGs list into four tiers based on our current understanding of their pathogenic impact: (A) pathogenic: well-known FGs or new members of common FG-FMs with definite pathogenicity in hematological malignancies or other tumors, e.g., BCR-ABL1 or new members of ABL1-FM; (B) likely pathogenic: rarely reported FGs or new members of rare FG-FMs in hematological malignancies or other tumors without functional verification, e.g., TBC1D15-RAB21, which was reported in acute promyelocytic leukemia, but no functional verification was reported [15]; or one of the partner genes was reported in hematological malignancies in other forms of abnormalities, such as mutation, e.g., ASXL2-ITSN2 (ASXL2 is frequently mutated in AML patients [16]; (C) uncertain significance: both fusion partners not reported before in hematological malignancies in any form of genomic alterations, e.g., Sample preparation Bone marrow samples were collected. Arriba assumes a polynomial relationship between the number of supporting reads and the level of
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