Integrating Medical Genetics Into the Care of Pediatric Oncology Patients

Cancer predisposition is an evolving field in pediatrics. Genomic studies in pediatric cancers began as recently as 2010. Prior to that, very few studies looked into the genetic makeup of pediatric cancers. With genomic sequencing of pediatric cancers, not only did oncologists learn what drives pediatric cancers, but it also gave a clue into populations of pediatric patients that are at risk to get cancers.

Harry Lesmana, MD, a pediatric oncologist and medical geneticist, recently joined Cleveland Clinic Children’s and the Center for Personalized Genetic Healthcare where he will focus on building a comprehensive program in Pediatric Cancer Predisposition Program. Dr. Lesmana completed a combined 5-year residency training in pediatrics and medical genetics at Cincinnati Children’s Hospital, and a 3-year fellowship training in pediatric oncology/hematology at St. Jude’s Children’s Research Hospital in Memphis, Tennessee.

In this Q&A, Dr. Lesmana discusses advantages and challenges of integrating medical genetics into the care of pediatric oncology patients, as well as his future plans at Cleveland Clinic Children’s. The interview has been edited for length and clarity.

When to consider genetic testing

CQD: When is genetic testing considered in pediatric oncology?

Dr. Lesmana: There are five scenarios that make us think about cancer predisposition in a patient. The first one, obviously, is family history — family history of the same type of cancer, or multiple cancers, in family members typically triggers the pediatric oncologist to refer the patient for genetic testing. The second is multiple cancers in a single child. The third reason is a cancer diagnosis at a very early age. Typically, cancers are diagnosed in a patient’s 40s, 50s or 60s, but if a patient is diagnosed in their 20s or 30s that obviously raises a concern for cancer predisposition, whether there is a family history or not.

The absence of a family history doesn’t mean that a patient does not have a cancer predisposition syndrome. The fourth reason is typical findings. These can be multiple hyperpigmented skin lesions that look like café au lait spots, which may point to a genetic syndrome called neurofibromatosis. This is just one example — there are multiple examples of typical findings that trigger us to think about certain genetics syndromes that put the patient at risk of cancer. As clinical geneticists we are trained to find the subtle findings that may point to the presence of a genetic syndrome. Lastly, the fifth scenario is a specific diagnosis of cancer that is highly associated with a cancer predisposition syndrome. For example, about 50% of those patients diagnosed with adrenal cortical carcinoma will have Li Fraumeni syndrome, one of the most common cancer predisposition syndromes.

CQD: What are the most common pathogenic germline variants in pediatric cancers?

Dr. Lesmana: The largest pediatric study to date looking into germline cancer predisposition mutations was published in the New England Journal of Medicine. In this retrospective study, out of 1,120 patients under the age of 20, 8.5% were identified to have cancer predisposition syndrome with mutation in TP53 gene (causing Li Fraumeni syndrome) as the most common. However, although this study was performed on unselected pediatric cancer population, the patient cohort was enriched by patients with hypodiploid leukemia where germline TP53 mutations are commonly identified. A further prospective study performed from 2017-2020, in an unselected pediatric cancer population, identified that the retinoblastoma (RB) gene mutation was the most commonly identified in pediatric population (unpublished data).

CQD: Does it make sense to advocate for broad genetic testing in pediatric cancer?

Dr. Lesmana: Here at Cleveland Clinic Children’s Department of Hematology & Oncology, we are trying to develop a program where all newly diagnosed pediatric cancer patients will be referred for genetics counseling within 30 days of diagnosis. This is so we can get a better understanding of the patient’s family history and the type of cancer. This does not mean that all patients will get genetic testing, because, realistically, it is hard to get it covered by insurance. For select patients, we will offer genetic testing, such as for patients with retinoblastoma. Hopefully, if we continue advocating for personal genetic testing, and there is good acceptance from insurance companies, then we should be able to provide genetic testing to any family who wants it.

Results may alter a patient’s treatment plan

CQD: How might a patient’s treatment be altered by findings from genetic testing?

Dr. Lesmana: Genetic testing does not only help us reach a diagnosis for a patient — it may also alter the treatment course. For instance, for a patient with Li Fraumeni syndrome who has a mutation in the tumor suppression gene p53, this patient is at risk of developing secondary cancer in the future because they are sensitive to ionizing radiation, such as CT scans or radiotherapy. We would like to spare these patients from getting additional radiation therapy and we will use a different additional [therapeutic] approach. Another example is in patients with leukemia. If we know that the leukemia is due to an underlying germline predisposition, such as changes in DNA repair genes, we know that these patients are at risk of significant toxicity from chemotherapy. So, there may be a need to modify the dose of their chemotherapy and, if they go into transplantation, we also need to reduce the intensity of their chemotherapy because we have seen so many patients with this condition decompensate during transplantation.