Background: Oncogenic fusions of
MAML2 with
CRTC1,
CRTC3,
YAP1, and
NR1D1 retain the
MAML2 transactivating domain (TAD) and are believed to drive aberrant gene transcription. While the oncogenic roles of these known fusions have been established, we aimed to identify novel
MAML2 fusions across a range of human malignancies. Methods: DNA and RNA sequencing were performed on tumor samples submitted to Caris Life Sciences.
MAML2 fusions were identified from RNA transcripts and filtered to include only known pathogenic fusions or recurrent, in-frame fusions containing a C-terminal
MAML2 TAD. Fusion burden was defined as the number of unique fusion isoforms per sample. Results: Among 180,124 tumor samples, 143 specimens harbored
MAML2 fusions with a
MAML2 TAD: >50% of specimens harbored known fusions, but novel fusions with
MTMR2 (31/143),
SESN3 (11/143),
CCDC82 (6/143),
FAM76B (4/143), and
ATXN3 (3/143) were also identified. Compared to the known fusions, the novel fusions generally had lower expressions (median: 8 vs. 13 junction reads/sample,
p = 0.0064), higher fusion burdens (median: 6 vs. 2 unique fusion isoforms/sample,
p < 0.0001), more frequent
TP53 co-mutations (80% vs. 11.5%,
p < 0.0001), and no clear association with the tissue of origin. Excluding
ATXN3::MAML2, the novel fusion partners were located near
MAML2 in the genome, likely arose from duplications or deletions, and occurred in samples harboring concurrent mutations. In contrast,
ATXN3::MAML2 arose via interchromosomal translocation, occurred in samples with a low fusion burden, and was not associated with TP53 mutations. Conclusions: We identified novel
MAML2 fusion partners, most of which likely represent passenger alterations, possibly arising from genomic instability or impaired p53 function. However,
ATXN3::MAML2 fusions, previously reported in a pre-cancerous pancreatic disease case, may represent a pathogenic alteration warranting further investigation.
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