Li Ding, PhD
Mutations known to be involved in hematologic malignancies were found in the blood cells of 2%-3% of individuals over age 40 and 5%-6% of those over age 70, according to a recent study from The Cancer Genome Atlas (TCGA) published in Nature Medicine
The analysis of 2,728 patients identified 64 mutations in 19 leukemia- and/or lymphoma-associated genes with variant allele fractions (VAFs) above 10%. In a site-specific analysis, 14 additional mutations with lower VAFs (2%-10%) were identified. Many of the identified genes, such as DNMT3A
, and GNAS
, are known drivers for hematologic malignancies, while others, such as PPM1D
, have not yet been implicated.
The authors on the study noted that while some individuals may be undergoing hematopoietic clonal expansion, most do not progress to disease.
“The power of this study lies in the large number of people we screened,” senior author Li Ding, PhD, of The Genome Institute at Washington University, said in a statement. “We don’t yet know whether having one of these mutations causes a higher than normal risk of developing blood cancers. More research would be required to better understand that risk.”
Individuals on the study had been diagnosed with cancer but the type was unknown — leukemia, lymphoma, or whether they had a hematologic malignancy at all. Patients (aged 10 to 90 at time of diagnosis) donated blood to TCGA before treatment so that mutations could not be associated with chemotherapy or radiation.
Significant differences in the presentation of mutations in leukemia- or lymphoma-associated genes were observed between age groups. Mutations were noted in 0.88% of individuals aged 40-49 (n = 341), 0.99% of individuals aged 50-59 (n = 707), 1.83% of individuals aged 60-69 (n = 767), 5.26% of individuals aged 70-79 (n = 475), and 6.06% of individuals aged 80-89 (n = 132).
However, this analysis may be underestimating the proportion of individuals with such mutations, the authors wrote, as they only identified small mutations. There remains a need to identify large structural variations or the insertions and deletions of chunks of genetic material associated with hematologic malignancies.
The authors on the study noted that a clinician must be careful in using blood as a surrogate reference. There is a risk of blood-specific variants being mistaken as germline variants in individuals without hematologic malignancies. Further, “germline alleles in cancer samples could be mistaken as tumor-specific variants when comparing to blood samples. Lastly, connections were made between mosaic PPM1D
mutations in lymphocytes and the predisposition to breast and ovarian cancers,” the authors wrote.
The authors stated that testing for mutations associated with leukemia and lymphoma would not predict an individual’s risk of a hematologic malignancy.
“We would not want anyone to think they should be screened for these mutations to understand their risk of leukemia or lymphoma,” Timothy Ley, MD, co-author and professor from Washington University said in a statement. “The ability to understand how mutations in these genes increase a person’s risk of blood cancers is a long way off, and genetic testing would be of no benefit at this time.”