Hematologic malignancies (also called blood cancers) are a vast group of cancers that involve the blood, bone marrow and immune system. These include leukemia, lymphoma and myeloma. Overall, hematologic cancers are a large portion of cancer diagnoses, with leukemia and lymphoma accounting for over 7% of all new cancer cases in the United States.
Until recently, these cancers were mostly thought to be sporadic. Few hereditary risk factors had been identified. However, with recent advances in genetic testing, a significant number of hematologic cancer predisposition genes have been discovered.
We currently know more about inherited risks for myeloid malignancies — specifically myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) — compared to lymphoid malignancies such as lymphoma and chronic lymphocytic leukemia (CLL).
Approximately 10% to 20% of MDS and AML cases are linked to an inherited genetic cause.
Inherited risk for MDS/AML
Several hereditary conditions can raise the risk of developing MDS or AML. These include bone marrow failure disorders that are associated with increased risks for leukemia, solid tumors, as well as other medical issues.
In the past, bone marrow failure syndromes were thought to only affect children and to be severe. But now, broader access to genetic testing has improved understanding of these conditions to also include individuals with more mild features and/or diagnosis of bone marrow failure later in life.
Telomere biology disorders (TBDs) are an example of a bone marrow failure syndrome with a wide spectrum of features and age of onset in individuals and families. They can be caused by an inherited mutation in over a dozen genes and can be characterized by an increased risk for bone marrow failure and MDS/AML as well as other features such as early greying of hair and pulmonary fibrosis.
There are genes associated with pre-existing platelet disorders in addition to increased risk for leukemia. For example, individuals with an inherited RUNX1 mutation typically present with a lifelong history of low platelets (thrombocytopenia).
Other genes associated with AML, like CEBPA, can cause acute-onset leukemia but do not appear to significantly increase risks for other types of cancer or medical issues.
Mutations in the DDX41 gene are another example. These raise the risk of developing MDS or AML later in life.
Why this matters for screening and treatment?
Knowing whether someone has an inherited risk for hematologic cancers is important for diagnosis and treatment.
The World Health Organization (WHO) now includes hereditary predisposition as a classification in diagnosing myeloid neoplasms. Many organizations have published clinical practice guidelines for screening and treatment of inherited forms of these diseases.
Finding a gene linked to MDS or AML can help guide treatment decisions. It’s especially important in treatment of patients diagnosed with AML, including therapy selection and planning for potential hematopoietic stem cell transplant.
Identifying a gene mutation associated with an increased risk for AML provides information on other risks, including pulmonary fibrosis with TBD. Additionally, identifying a gene mutation associated with an increased risk for AML helps identify at-risk family members and can also inform donor selection for stem cell transplant.
For example, genetic testing for family members may indicate a need for more frequent blood counts (CBCs), annual clinical exams with a hematologist-oncologist or bone marrow biopsies.
Should you get genetic testing?
Genetic testing should be considered for anyone with a personal or family history of MDS or AML, especially if the cancer was diagnosed at a younger age.
Other signs that testing might be helpful include:
- A longstanding history of low blood cells (cytopenias)
- Aplastic anemia
- Personal or family history of certain features of bone marrow failure syndromes such as short stature, early greying of hair, liver or pulmonary fibrosis, brittle nails or differences in skin pigmentation
Genetic counseling and testing are available at Northside Hospital Cancer Institute through the Cancer Genetics Program. Learn more.
