Genetic Mutations Discovered That Drive Inherited Leukemias in Older Patients

Cleveland Clinic researchers contradict notion that most adult myeloid neoplasms occur sporadically

Cleveland Clinic researchers have identified a new class of genetic mutations associated with an increased risk for development of leukemia later in life.

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The implications go beyond the significant discovery of new germline and somatic mutations linked to leukemogenesis. Jaroslaw Maciejewski, MD, PhD, and colleagues report a more surprising finding: A portion of leukemia cases in older adults normally considered sporadic might instead be due to inherited genetic mutations.

“It is a novel finding that is perhaps counterintuitive to what we think when we see an older patient with leukemia,” says Dr. Maciejewski, Chairman of Cleveland Clinic’s Department of Translational Hematology and Oncology Research. “It is remarkable that, despite patients having this defective gene, leukemia develops later in life. This is unusual for inherited leukemias and cancers, which typically present in childhood.

“This discovery suggests that more leukemia/cancer predisposition genes exist, and thus the role of inherited gene variants in cancer likely will be recognized as much greater,” Dr. Maciejewski says.

Inherited and somatic changes

Until now, researchers had routinely assumed that most cases of adult myeloid neoplasms — including myelodysplastic syndromes (MDS), which predominantly affect the elderly — occur sporadically. Familial MDS cases have rarely been reported.

During routine genetic screening of a series of leukemia patients at Cleveland Clinic, investigators identified a mutated gene on chromosome 5q, DDX41, associated with development of MDS. This by itself was a novel finding because DDX41 was never before associated with any cancers.

It turns out that both inherited and somatic changes to DDX41 could be culprits.

Dr. Maciejewski and colleagues studied multiple families affected by MDS/secondary acute myeloid leukemia (sAML) and found DDX41 mutations in some of them. Consequently they performed targeted genetic screening on a cohort of 1,045 patients with myeloid leukemia and found that 27 had DDX41 alterations. Moreover, they discovered that some patients’ DDX41 mutations were not inherited but were acquired by the leukemia cells.

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The researchers propose that a “first hit” inherited mutation and “second hit” somatic changes to DDX41 likely cause these leukemia cases to develop in older patients, supporting the prospect of a familial predisposition mechanism behind these malignancies.

Broader implications

The surprising familial etiology for some leukemias could also apply to other cancers that develop later in life, Dr. Maciejewski says. “This discovery points out that most likely there will be many more genes that run in families that predispose people to late cancers.” The challenge, he adds, will be the higher level of clinical suspicion and sleuthing necessary to identify them.

While genetic testing of pediatric patients and their relatives in families affected by known inherited malignancies is commonplace, Dr. Maciejewski says physicians could consider genetic screening of older patients with myeloid neoplasms. This approach could uncover a new etiology for some cancers and play a role in patient and family counseling. “Some of the inherited cancers might also appear later in age and mask actual familial disease,” he says.

Although the exact mechanism that causes DDX41 to spur some leukemias remains unknown, the findings demonstrate that either deletion or mutation of this gene can induce myelodysplastic syndrome and leukemia with a long latency and significant penetrance.

“Both somatic and germline mutations indicate that DDX41 is a tumor suppression gene and an important driver in myeloid malignancies,” the authors wrote in their study, Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms, published in the May 11, 2015, issue of Cancer Cell.

Approximately half of the patients with germline DDX41 mutations also acquired somatic DDX41 mutations, which occurred more frequently in patients with advanced MDS, the researchers reported. Germline DDX41 mutations were associated with somatic mutations of other cancer-associated genes: TP53, RUNX1 and LUC7L2.

Some treatment promise

Although DDX41 mutations were associated with advanced disease and poorer prognosis in the study, there was some positive news as well.

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Dr. Maciejewski and his team of Cleveland Clinic and other national and international collaborators also found that the presence of the mutations was associated with treatment response to lenalidomide. Lenalidomide is already approved by the Food and Drug Administration for the treatment of patients with deletion 5q myelodysplastic syndromes, multiple myeloma and relapsed or refractory mantle cell lymphoma.

Further research will be needed to elucidate lenalidomide’s potential as a treatment for patients with DDX41 mutations, Dr. Maciejewski says.

Research and referral

If the genetic screening and workup of patients with myelodysplastic syndrome, secondary acute myeloid leukemia or potentially inherited leukemia in older-age onset are outside the expertise or comfort zone of an oncologist, Dr. Maciejewski suggests referral. Affected patients and their families can generally find a higher level of care at an academic medical center with dedicated cancer and genomic expertise.

Dr. Maciejewski acknowledges that diagnosing inherited, late-onset cancers will likely remain challenging in the near future because the findings are so new. DDX41 and its role in inherited, later-in-life leukemias could be just the beginning.

KEY POINTS IN THIS ARTICLE

  • Most cases of adult myeloid neoplasms, including myelodysplastic syndromes (MDS), have been presumed to occur sporadically.
  • Cleveland Clinic researchers have identified a mutated gene, DDX41, associated with development of MDS.
  • The researchers propose that a “first hit” inherited mutation and “second hit” somatic changes to DDX41 likely cause MDS to develop in older patients, supporting the prospect of a familial predisposition mechanism behind these malignancies.

Dr. Maciejewski is Chairman of Cleveland Clinic’s Department of Translational Hematology and Oncology Research and a staff member of the departments of Clinical Pathology and Hematology and Medical Oncology. He is a Professor of Medicine at Cleveland Clinic Lerner College of Medicine. He can be reached at maciejj@ccf.org or 216.445.5962.

Photo Credit: ©Russell Lee