ITDs

Internal tandem duplications (ITDs) are a type of genetic alteration in which a segment of DNA within a gene is duplicated in tandem and inserted adjacent to the original copy. The result is an in-frame insertion that adds extra amino acids to the encoded protein, frequently altering its function or regulation. ITDs are observed in a range of cancers, most notably in hematologic malignancies, where they can drive abnormal signaling and cellular behavior.

The best characterized ITD occurs in the FLT3 gene, which encodes a receptor tyrosine kinase. FLT3-ITD mutations lead to constitutive receptor activation and downstream signaling through pathways such as MAPK, PI3K/AKT, and STAT5, promoting proliferation and survival of leukemic cells. FLT3-ITD is present in a substantial subset of acute myeloid leukemia patients and is associated with an adverse prognosis, particularly when the mutant allele burden is high or the insertion is long. ITDs have also been reported in other genes and cancers, but their clinical implications are less well defined.

Detection and reporting of ITDs rely on DNA- or RNA-based methods. Fragment analysis by PCR and capillary electrophoresis is commonly used to size the duplication, while sequencing (including next-generation sequencing) determines the exact sequence and allows assessment of mutant/wild-type allele ratio, which can influence prognosis and treatment decisions.

Therapeutically, identification of FLT3-ITD can guide targeted therapy with FLT3 inhibitors, such as midostaurin or gilteritinib, typically used in combination with standard chemotherapy or as monotherapy in relapse. Ongoing research aims to better define ITD biology, refine detection, and optimize management across cancer types.