Genetic Susceptibility to Leukemia in Pediatrics

Kim Nichols, MD

As part of our coverage of the ASH Annual Meeting held December 3rd to 6th in San Diego, today we are speaking with Kim Nichols, MD, director of the Cancer Predisposition Division at St. Jude Children's Research Hospital. At this year’s meeting, Dr. Nichols will be participating in a session on genetic susceptibility to leukemia. 

-Interviewed by Leah Lawrence

OncoTherapy Network: How common are hereditary cancers in the pediatric arena?

Dr. Nichols: Currently, it is estimated that somewhere between 8% to 10% of children with cancer have an underlying genetic predisposition. However, the chance of finding an underlying predisposition varies depending on the type of tumor that the child has. For example, we know that about 40% of children with an eye cancer known as retinoblastoma have a hereditary form of the disease. Similarly, somewhere between 50% and 80% of children with a rare form of adrenal cancer known as adrenal cortical carcinoma develop the disease due to the presence of a genetic condition known as Li-Fraumeni syndrome. In contrast, for children or adults with leukemia, the odds of identifying an underlying genetic condition are somewhat lower, probably closer to 3% to 4% of all cases. It is possible that overtime as we learn more about different genes in the genome this number will increase.

OncoTherapy Network: People more commonly hear about hereditary cancers in solid tumors, what are some of the most common hematologic hereditary cancer syndromes?

Dr. Nichols: That is a very good question. There are currently several different hereditary conditions that can increase the risk for leukemia. In some of these conditions, leukemia is one of a number of different cancers that can develop. Conditions in which this is the case include Li-Fraumeni syndrome, which is caused by germline mutations in the TP53 tumor suppressor gene. Individuals with Li-Fraumeni syndrome are at increased risk to develop a variety of solid cancers, such as early onset breast cancer, soft tissue and bone sarcomas, brain cancer, and adrenal cortical carcinoma. However, a subset of patients with this condition can develop leukemia, most commonly B acute lymphoblastic leukemia.

Another excellent example includes a condition known as biallelic mismatch repair deficiency. In this condition, affected individuals are carrying damaging mutations affecting both copies of genes known as MLH1, MSH2, MSH6, or PMS2. These are critical genes involved in the repair of DNA base pair mismatches. Individuals with biallelic mismatch repair deficiency are at increased risk to develop early onset brain and gastrointestinal cancers, as well as variety of hematologic cancers, including acute leukemia and non-Hodgkin lymphoma.

On the other hand, in other hereditary conditions, hematopoietic cancers such as leukemia can be the sole manifestation of the disease. Examples of these types of conditions include familial AML [acute myeloid leukemia] due to mutations in the CEBP alpha gene. There is a new condition called thrombocytopenia type 5. This is a condition typified by thrombocytopenia and leukemia predisposition and it’s caused by germline mutations in ETV6. Finally, familial platelet disorders and associated myeloid malignancy caused by germline mutations in RUNX1. There are all examples of a multitude of rare conditions that increase the risk for leukemia or other hematopoietic cancers.

OncoTherapy Network: What factors trigger consideration of a hereditary syndrome in pediatric cases?

Dr. Nichols: This is an excellent question. In my mind, there are three major factors that should trigger consideration of a hereditary syndrome in a child or an adult with cancer. These three factors include: 1) the presence of a positive family history of cancer, 2) specific features of the cancer itself, and, 3) certain physical or medical findings. Hematologists and oncologists should consider each of these factors when evaluating a patient and refer patients to a cancer genetic specialist when there is a suspicion of an underlying syndrome.

In terms of family history, it is important for the physician to take time to collect and document which individuals in the patient’s family have developed cancer, the type of cancer, and the age of cancer onset. Ideally, a three-generation pedigree should be drawn. It is also important that the physician update the family history every 1 to 2 years because these can evolve over time. Some features of the family history that should raise suspicion of an underlying condition include the presence of multiple relatives spanning several generations along either the maternal or paternal lineage with the same or related types of cancer, or the presence of early onset, bilateral, or multiple primary caners.

Features of the tumor that are suggestive of underlying syndrome involvement include bilateral involvement of paired organs-like both breasts, both eyes, both kidneys-multifocal tumors, multiple primary tumors, and certain therapy-associated cancers including secondary leukemia.

Finally, certain tumor histologies can trigger concern. Good examples include adrenal cortical or choroid plexus carcinomas, which are caused by germline TP53 mutations in a high proportion of cases.

Lastly, many hereditary syndromes are associated with nononcologic manifestations including characteristic physical findings, like café au lait spots, under or overgrowth, and cognitive or developmental delays. For many genetic conditions it is important to note that the defining manifestations may precede a diagnosis by several years; therefore, I think it is really important that primary providers, be it hematologists or general physicians, be aware of the presence of these physical features in their patients and consider the possibility of an underlying syndrome.

OncoTherapy Network: If a hereditary syndrome is already known in a family, what steps can be taken for prevention of these diseases?

Dr. Nichols: If a hereditary syndrome is known to be present within the family, there are several steps that can be taken for prevention. First, it is important to determine who in the family is affected. This will involve genetic counseling and testing of blood relatives of an affected individual. Once an individual tests positive, that person can then be monitored for cancer formation. Although, monitoring will not prevent cancers from occurring, monitoring does have the potential to detect cancer at the earliest stages when they are smaller and most easily treated.

For patients with certain conditions it is also possible to prevent cancers from happening. This most commonly involves the surgical removal of organs that are considered to be at risk. For example, prophylactic removal of the thyroid gland in children with multiple endocrine neoplasia type 2 who are at increased risk to develop thyroid cancer. Alternatively, one can perform a colectomy  in a young adult with familial adenomatous polyposis. These young adults are at greatly increased risk to develop gastrointestinal polyps and colon cancer. For each of these conditions, multiple endocrine neoplasia and familial adenomatous polyposis studies have shown that there is a significant drop in the risk for cancer thanks to these preventative surgical measures.

For children or adults with leukemia predisposing conditions, one step that can be taken is allogeneic stem cell transplantation. By replacing the child’s or adult’s at-risk organ, so in this case the bone marrow, with bone marrow from a healthy sibling or other donor, one can lessen or eliminate the chances for leukemia formation. However, when considering allogeneic stem cell transplantation in a sibling or related donor it is very important to test the sibling or relative for the presence of the known familial mutation prior to completing the transplant. Only siblings or relatives who test negative should be chosen as stem cell donors.

OncoTherapy Network: Where is the field with researching these leukemias? What are some of the exciting things on the horizon for these hereditary syndromes?

Dr. Nichols: There are several ongoing and exciting areas of research related to hereditary leukemia. For example, many investigators, including myself, are searching for new genetic conditions associated with leukemia development. While many of these conditions are thought to be rare, the genes that are affected are often very important for normal blood cell development. By identifying genes and studying how predisposing mutations affect their function, we may better understand the pathways that contribute to leukemia formation. Hopefully, in the future, it will be possible to use this information to develop new treatments or possibly even preventive medication.

Another area of investigation is focused on how best to monitor for the onset of leukemia in a patient with an underlying predisposition. Currently, we have no really good methods. However, with the advent of high-throughput approaches, studies are underway to screen the blood for new mutations that could be harbingers for leukemia.

Finally, one of the most exciting areas of research involves the topic of gene editing. Through cutting-edge gene editing technologies, it is now possible to correct or reverse a genetic mutation within a cell type of interest. By doing this, it may be possible to prevent a disease from happening. For example, if one were to correct the mutation within a leukemia predisposing gene in the bone marrow cells of an individual with a hereditary leukemia syndrome and then transfer these corrected cells back into that individual, it might be possible to prevent leukemia from ever happening. These are really exciting times for genetics and other forms of research related to hereditary forms of leukemia.

OncoTherapy Network: Thank you again for speaking with us today about genetic susceptibility to leukemia in pediatrics.

Dr. Nichols: I appreciate the opportunity to speak with you.