Study reveals inherited risk of leukemia

Inherited mutations that increase the risk of developing a dangerous blood cancer are more common than previously appreciated, a new study reveals.

Researchers analyzed acute myeloid leukemia samples from nearly 400 adult patients and found that more than 13% of them had inherited genes that likely predisposed them to the cancer.

The mutations occurred across the entire age spectrum of subjects in the study group, called Beat AML 1.0. The findings support the need for routine screening for inherited predisposition genes in all patients with acute myeloid leukemia, said senior author Anupriya Agarwal, Ph.D. The researchers published their results in the journal Blood.

For people with AML — and their families — the diagnosis of an inherited predisposition has significant implications. For instance, it’s important to know if family members have inherited a susceptibility gene before they serve as donors for bone marrow or stem cell transplant. It’s also important for genetic counseling of family members and making decisions about getting on a schedule of testing for signs of leukemia developing.

Anupriya Agarwal, Ph.D.

“If you know that a patient has an inherited predisposition, we can monitor them, and maybe catch leukemia early,” Agarwal said. It’s also possible, she said, that some of the mutations her team found could identify patients who would benefit from certain targeted therapy drugs. Agarwal is an associate professor in the OHSU School of Medicine, Division of Oncological Sciences. Her lab collaborated on the research with others at OHSU, the University of Colorado, the University of Texas Southwestern Medical Center and the University of Utah Huntsman Cancer Institute.

The team reached their findings by analyzing gene sequencing data on cancer tissue samples in comparison with normal tissues from 391 people with AML. They focused on 291 genes associated with cancer predisposition. They then completed the monumental job of manually classifying more than 1,500 sequence variations in 228 genes. It is the largest analysis of its kind of an AML patient population, the researchers said. In 2018, the journal Nature published the somatic mutation landscape of these AML patients, a study led by Jeff Tyner, Ph.D., Shannon McWeeney, Ph.D., and Brian Druker, M.D., and funded by the Leukemia & Lymphoma Society.

In the new study, 53 of the 391 people with AML, or 13.6 percent, harbored inherited cancer predisposing gene mutations. More than 6 percent of the subjects had gene variations considered clinically actionable, that is, identification of the mutation can help the patient receive more appropriate care. The most common of these were DDX41 mutations, which doctors already look for in related stem cell donors to prevent donor-derived leukemia.

Nearly two-thirds of the study subjects harbored at least one inherited mutation of uncertain significance in one of the genes associated with cancer predisposition. The high rate underscores the need for further studies to understand these gene variations, the researchers said. As part of the study, they demonstrated that structural analysis using a protein modeling approach may be useful in prioritizing variants of uncertain significance for deeper investigation.

Twenty-two patients had mutations in DNA damage response genes, which is significant because there are therapies under development that target the signaling pathways associated with these genes. Understanding the role of DNA damage response pathway mutations in blood cancers “could lead to the extension of specific treatment approaches that are efficacious for this subgroup, such as PARP inhibitors, which, for unselected AML, have limited activity, at least in the single-agent trial setting,” Anna Brown, Ph.D., at the University of South Australia wrote in an editorial on the study.

The findings “should prompt quick change to our clinical practice,” Lucy Godley, M.D., Ph.D., at the University of Chicago wrote in another commentary on the study. She said it’s now necessary to incorporate germline predisposition testing into the standard AML diagnostic workup.

Further reading:

Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML by Fei Yang, Nicola Long, Tauangtham Anekpuritanang, Daniel Bottomly, Jonathan C. Savage, Tiffany Lee, Jose Solis-Ruiz, Uma Borate, Beth Wilmot, Cristina Tognon, Allison M. Bock, Daniel A. Polly, Saikripa Radhakrishnan, Srinidhi Radhakrishnan, Prapti Patel, Robert H. Collins, Srinivas Tantravahi, Michael W. Deininger, Guang Fan, Brian Druker, Ujwal Shinde, Jeffrey W. Tyner, Richard D. Press, Shannon McWeeney, and Anupriya Agarwal. Blood (Feb. 24, 2022)

And the germline beat (AML) goes on by Anna L. Brown. Blood (Feb. 24, 2022)