Leukemia is a cancer of the blood-forming tissues, where the bone marrow produces a large number of abnormal blood cells. While genetic changes cause all leukemias, only a small portion of cases involve an inherited predisposition passed down through a family. Understanding the difference between these acquired and inherited genetic changes is necessary to determine an individual’s risk and management plan.
Sporadic Versus Inherited Causes
Most leukemia cases are sporadic, meaning the genetic mutations are acquired during a person’s lifetime. These acquired, or somatic, mutations occur spontaneously in blood-forming cells due to aging, environmental factors, or errors in DNA replication. In contrast, hereditary leukemia involves a germline mutation, which is a genetic change present in virtually every cell of the body and passed from parent to child.
Hereditary leukemia is rare, accounting for approximately 5 to 10% of all blood cancers, including leukemia and myelodysplastic syndrome (MDS). A germline mutation does not guarantee leukemia will develop, but establishes a significant predisposition. This is often explained by the “two-hit” hypothesis, where the inherited mutation acts as the first “hit.”
The second “hit” is an acquired somatic mutation in the same or related genes that occurs later in life. This second event is necessary to transform the predisposed cell into a cancerous one. Because individuals with an inherited predisposition already have the first “hit,” they are at a much higher risk and often develop the disease at an earlier age compared to those with sporadic leukemia.
Specific Familial Leukemia Subtypes
Some forms of leukemia have a direct familial or hereditary subtype, linked to specific, highly penetrant gene mutations. Familial Acute Myeloid Leukemia (AML) is one of the most recognized hereditary forms, often associated with germline mutations in genes like CEBPA, RUNX1, or GATA2. A mutation in the CEBPA gene, which regulates blood cell development, confers a lifetime risk of developing AML that can exceed 90% for some variants.
The RUNX1 gene mutation is associated with Familial Platelet Disorder with predisposition to AML (FPD/AML), often presenting with low platelet counts before leukemia onset. Familial Chronic Lymphocytic Leukemia (CLL) is also recognized, though the specific inherited genes are less defined than in AML, and the risk involves multiple genetic factors. Familial Acute Lymphoblastic Leukemia (ALL) is less common, but mutations in genes like PAX5 and ETV6 have been implicated in some families.
The pattern of inheritance and the specific gene involved allow for targeted genetic testing and surveillance protocols. Identifying these germline mutations is important for the affected individual’s treatment and for the risk assessment of their family members.
Inherited Syndromes That Increase Risk
Many hereditary conditions involve defects in DNA repair or cell growth regulation, significantly increasing the overall risk of developing leukemia. Down Syndrome (Trisomy 21) is a common example, where children have a 10 to 30 times higher risk of developing ALL or AML. The increased gene dosage from the extra chromosome 21 copy is thought to disrupt normal blood cell development.
Fanconi Anemia is a rare inherited disorder caused by mutations in DNA repair genes, making cells highly sensitive to damage. Individuals with Fanconi Anemia have an elevated risk of developing AML and Myelodysplastic Syndrome. Similarly, Bloom Syndrome, caused by a mutation in the BLM gene, results in a DNA repair defect, leading to chromosome instability and an increased risk of ALL and AML.
Li-Fraumeni Syndrome, typically caused by a germline mutation in the TP53 tumor suppressor gene, predisposes individuals to a wide range of cancers, including ALL and AML. The TP53 gene normally regulates cell division and triggers cell death in damaged cells, and its inactivation impairs the body’s ability to prevent tumor formation.
Neurofibromatosis Type 1 (NF1), caused by a mutation in the NF1 gene, is also associated with an increased risk of developing juvenile myelomonocytic leukemia (JMML), a rare form of leukemia, as well as AML.
Genetic Screening and Family Risk Management
When a hereditary leukemia predisposition is suspected due to a strong family history or young age of diagnosis, genetic counseling is the first step. A genetic counselor assesses the risk, discusses testing implications, and guides the patient through the process. Germline testing is typically performed on blood or saliva, but if the patient has active leukemia, a non-hematopoietic source like a skin biopsy is necessary to detect the inherited mutation.
A positive test confirms the presence of a predisposition gene and allows for the identification of at-risk family members, who have a 50% chance of carrying the same mutation. For high-risk carriers, management shifts to proactive surveillance, aiming for early detection. This may involve:
- Regular blood counts.
- Physical exams.
- Periodic bone marrow biopsies, depending on the specific gene mutation and associated risk.
Surveillance protocols are tailored to the specific syndrome. Carriers of the CEBPA mutation may require different monitoring than those with Fanconi Anemia, which also involves screening for other associated non-hematologic cancers. The goal of early monitoring is to identify the development of leukemia or a pre-leukemic condition, such as MDS, at its earliest, most treatable stage.