AML cells
A large study of adults with acute myeloid leukemia (AML) correlates cancer-related genetic mutations with subtypes of AML defined by the presence of specific cytogenetic abnormalities.
Researchers combined the cytogenetic abnormalities that define each of 34 AML subgroups with the mutation status of 80 cancer-related genes to produce an “oncoprint,” a tabular summary of the mutations associated with each cytogenetic group.
This allowed the researchers to identify genetic differences among the 34 subgroups and unexpected associations between the AML subsets and specific genetic mutations as well as gene functional groups.
The researchers believe their findings, published in Leukemia, might help guide mutation testing and treatment decisions in the future.
The study involved 1603 newly diagnosed adult AML patients who were treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials in multiple centers across the US. Most patients (n=1080) were under age 60.
The researchers classified the patients into 34 karyotype subgroups within 5 major cytogenetic groups—cytogenetically normal (CN) AML, complex karyotype (CK) AML, core-binding factor (CBF) AML, AML with balanced translocations or inversions other than those associated with CBF-AML, and AML with unbalanced chromosomal abnormalities detected in non-complex karyotypes.
The team sequenced pretreatment bone marrow or peripheral blood samples from each patient to learn the mutational status of 80 cancer- and leukemia-related genes.
The mutations were assigned to 1 of 9 categories based on the gene’s biological function—for example, methylation-related, cohesin complex, chromatin remodeling, and tumor-suppressor genes.
The researchers identified 4390 mutations, with a median of 3 mutations per patient.
Overall, the most frequently mutated genes that contributed to AML in this cohort belonged to the methylation group.
The researchers observed a high incidence of mutations in methylation-related genes in patients with CN-AML, CK-AML, or unbalanced chromosomal abnormalities.
In contrast, mutations in methylation-related genes were almost absent in CBF-AML patients and were rather rare in patients with non-CBF-AML-related balanced translocations or inversions.
Mutations in spliceosome genes were frequent in patients with unbalanced chromosomal abnormalities, especially those with sole trisomy of chromosomes 4, 8, 11, 13, or 21.
“Our study summarizes cytogenetic and mutational information of 1603 AML patients in a single image,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.
“The identification of key mutational features of each subgroup may help us to better understand the pathogenesis of the different AML types and provides a wealth of information for ongoing and future research.”
