A higher rate of mutations has been detected in the 2% of children with acute lymphoblastic leukemia who have intrachromosomal amplification of chromosome 21, a disease subtype associated with a high risk of relapse in standard therapy.
Patients with iAMP21 had a mean of 24.9 mutations per case for iAMP21 patients (range 5-51), including a high frequency of RAS pathway mutations. For their research, Sarra Ryan, PhD , of the Northern Institute for Cancer Research at Newcastle University in Newcastle Upon Tyne, UK, and her colleagues, conducted whole-exome sequencing on eight samples from patients with iAMP21 to identify some 199 somatic mutations, nearly two-thirds of which had not previously been reported in cancer ( Leukemia 2016 Sep;30;1824-31 ).
RAS pathway mutations occurred in six of the eight iAMP21 samples, including three mutations never before reported. Targeted sequencing of diagnostic samples from 42 iAMP21-ALL patients showed that 60% (n = 25) harbored 42 distinct mutations within the RAS signaling pathway.
Dr. Ryan and her colleagues also showed that MEK1/2 inhibition with the drug selumetinib reduced the viability of iAMP21-positive cells with phosphorylated ERK (pERK) expression in xenograft samples taken from iAMP21 patients with RAS pathway mutations, while cells from iAMP21 patients without RAS mutations did not respond to selumetinib.
This study, Dr. Ryan and her colleagues wrote, is the first “to explore the mutational landscape of iAMP21-ALL. A high incidence of RAS pathway mutations was observed against which targeted RAS/RAF/ERK pathway inhibitors may offer an additional therapeutic strategy to the current highly toxic chemotherapeutic agents given to these high-risk patients.”
Dr. Ryan and her colleagues’ research was supported by Bloodwise, a UK cancer charity, and the European Research Council. None of its authors disclosed conflicts of interest.