Dr Kuykendall on Molecular Testing in Systemic Mastocytosis

Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the importance of testing for mutations in KIT and other genes in patients with systemic mastocytosis.

Most patients with systemic mastocytosis or advanced systemic mastocytosis have a driver mutation in the KIT oncogene, commonly at codon 816, although other KIT mutations can arise and are included in the diagnostic criteria for this disease, Kuykendall says. Diagnosing a patient with systemic mastocytosis involves determining whether they have a KIT mutation, which can also drive treatment decisions, as these mutations are often sensitive to KIT-targeted therapies, Kuykendall explains.

However, many standard genetic testing methods are not sensitive enough to detect KIT mutations, which can be present at low levels, especially in the peripheral blood, Kuykendall notes. Highly sensitive mutational testing methods, such as digital droplet polymerase chain reaction, which can detect mutations at allele frequencies as low as 0.03%, are necessary to accurately determine whether a patient has KIT-mutated systemic mastocytosis, Kuykendall emphasizes. Less sensitive tests, such as traditional next-generation sequencing (NGS), which can detect mutation allele frequencies at levels as low as 5%, and Sanger sequencing, which can detect allele frequencies at levels as low as 15%, may falsely determine that a patient with KIT-driven disease does not have a KIT mutation, Kuykendall says.

In addition to testing for KIT mutations, broader NGS sequencing in the bone marrow or peripheral blood can determine whether patients with systemic mastocytosis have additional mutations driving associated hematologic neoplasms, Kuykendall explains. Although additional mutations in genes such as SRSF2, ASXL1, and RUNX1 are prognostic for worse disease outcomes, other mutations may be associated with potential treatment options for these hematologic neoplasms, Kuykendall notes. Molecular testing in systemic mastocytosis is crucial for improving patient outcomes, as many molecular drivers of this disease have been well defined, Kuykendall concludes.