Why is detecting known and novel fusions important?

Gene fusions, both known and novel, act as driver mutations in multiple cancer types by causing:

• Deregulation of one of the partner genes. For example, increased expression of an oncogene due to upstream fusion of a strong promoter.
• Formation of an oncogenic fusion protein. For example, constitutive activation of a receptor tyrosine kinase due to fusion of a dimerization domain.
• Inactivation of a tumor suppressor. For example, truncation of a functional domain.

Many known driver fusions involve a targetable partner. A “novel fusion” describes a transcript in which an unknown partner is fused to a gene that is known to be involved in the specific cancer type. For example, an unknown NTRK3 fusion that leaves the kinase domain intact is likely to be functionally involved in tumor origination or progression.