Novel MAML2 Fusions in Human Malignancy

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Oncogenic MAML2 fusions, retaining the MAML2 transactivating domain (TAD), are known drivers of aberrant gene transcription.
• Established oncogenic roles exist for MAML2 fusions with CRTC1, CRTC3, YAP1, and NR1D1.
• The study aimed to discover novel MAML2 fusions in diverse human malignancies.

Purpose of the Study:

• To identify and characterize novel MAML2 fusion partners across a broad spectrum of human cancers.
• To compare the characteristics of novel MAML2 fusions with previously identified ones.

Main Methods:

• DNA and RNA sequencing of 180,124 tumor samples.
• Identification and filtering of MAML2 fusions, focusing on pathogenic or recurrent in-frame fusions with a C-terminal MAML2 TAD.
• Definition of fusion burden as the count of unique fusion isoforms per sample.

Main Results:

• 143 specimens harbored MAML2 fusions with a MAML2 TAD.
• Novel fusions identified with MTMR2, SESN3, CCDC82, FAM76B, and ATXN3.
• Novel fusions exhibited lower expression, higher fusion burden, and more frequent TP53 co-mutations compared to known fusions, except for ATXN3::MAML2.
• ATXN3::MAML2 arose via interchromosomal translocation and lacked TP53 mutation association.

Conclusions:

• Novel MAML2 fusion partners were identified, with most likely being passenger alterations linked to genomic instability or p53 dysfunction.
• The ATXN3::MAML2 fusion, previously noted in a pre-cancerous pancreatic condition, warrants further investigation as a potential pathogenic alteration.