Overview of Predisposition to Pediatric Cancer

Educational Objectives

The goal of this program is to improve detection of cancer predisposition syndromes (CPS) in pediatric patients. After hearing and assimilating this program, the clinician will be better able to:

1. Use tumor profiling to identify patients with CPS.
2. Refer candidates for genetic testing for CPS based on physical findings and family history.
3. Differentiate cancer types with probable germline mutations from those without.

Summary

Characteristics of pediatric cancer: pediatric cancer is distinct from cancer in adults; constitutes <1% of all cancers diagnosed in the United States (US); ≈16,000 children are diagnosed annually; over the last 50 yr, 5-yr survival rates have improved from 10% to 20% to 85%; the current focus is on improving outcomes for the remaining 15% through early diagnosis and identification of pediatric cancer patients who are at high risk; leukemia and lymphoma are the most common types of pediatric cancers, followed by central nervous system malignancies; not strongly linked to lifestyle and environmental risk factors; treatment of pediatric cancer often is more effective than in adults; up to 95% of children with acute lymphoblastic leukemia are cured, compared with a much lower survival rate in adults; brain tumors are an exception to this trend; the US Food and Drug Administration recently mandated that every biological agent or drug in clinical trials that has potential for pediatric use must plan to enroll pediatric patients; a major concern is long-term adverse effects of chemo- and radiation therapy (RT); safer treatments that spare patients from the effects of high-dose chemotherapy or RT are being pursued, with goals of improving quality of life and minimizing risk for secondary malignancies

Cancer predisposition syndrome (CPS): a genetic disorder in which a germline mutation in one or more genes predisposes an individual to cancer; previously 1% to 2% of children with cancer were thought to have germline predispositions, but >100 distinct syndromes have been discovered recently, syndromic and nonsyndromic; clinical oncologists play a greater role than clinical geneticists in identification of patients or families at elevated risk of developing cancer; risk for cancer varies among CPS and is difficult to quantify; risk may depend on the genes that are involved, or relate to specific genotype-phenotype correlations; international and national surveillance guidelines reflect expert consensus rather than being evidence based; tumor profiling — increasingly used in the management of pediatric cancer; has contributed to the identification of patients with CPS; however, in many families in which multiple members are affected by cancer, the underlying cause remains unknown despite extensive clinical evaluation and genetic testing; causes may be epigenetic or multigenic

Study data: the rate of germline predisposition has been reported at 8.5% to 20%; in general, 10% to 20% pediatric patients have an underlying CPS; in a recent study that included 300 unselected cases, an underlying CPS was identified in ≈18%; further research is needed to determine whether genes normally associated with adult cancers (eg, BRCA1, CHEK2) are associated with predisposition to pediatric cancer

Pediatric cancer predisposition services: provided by many centers in the US, Canada, and Europe; the goal is to provide a comprehensive evaluation of patients with personal or family histories of cancer; a genetic counselor reviews the patient’s family history; if necessary, an oncologist or clinical geneticist performs a physical examination; findings determine whether genetic testing is warranted; the service also includes provision and coordination of genetic testing along with pre- and post-test counseling, coordination of cascade testing for family members at risk, and provision of cancer surveillance (depending on the diagnosis of the proband), using guidelines that are modified according to the individual circumstances; referrals to appropriate specialists are made; overall objectives are early detection and referral to treatment, with resulting improvement in outcomes

Indicating for referral and testing: patients without cancer — physical features consistent with CPS should be explored; examples include those with multiple polyps (possible mutation of the APC gene), café-au-lait spots (indicative of neurofibromatosis type 1 [NF1] or 2, or other neurocutaneous disorders), hemihypertrophy (consider Beckwith-Wiedemann syndrome [BWS]), macrocephaly in autism spectrum or PTEN disorders, or radial ray anomalies in, eg, Fanconi anemia; patients with cancer — bilateral or multifocal cancers or multiple primary cancers; cancers normally found in adults (eg, pancreatic carcinoma) in a pediatric patient; specific types of syndrome-associated cancers; findings on tumor profiling that suggest germline predisposition

Family history and CPS: pattern of occurrence — underlying CPS is suggested in cases of, eg, families with 3 generations affected by cancer, ≥3 relatives with the same type of cancer on the same side of a family, >1 first-degree relatives of the patient with the same cancer; any earlier-than-expected age of onset of cancer is suggestive of CPS; ethnicity, eg, Ashkenazi Jewish background, may be suggestive as well

Cancer types: 40% to 50% of patients with adrenocortical carcinoma or choroid plexus carcinoma have a germline TP53 mutation; patients with treatment-resistant rhabdomyosarcoma, particularly embryonal rhabdomyosarcoma with anaplastic features, are at increased risk for CPS; among patients with atypical teratoid and malignant rhabdoid tumors, ≈55% have a syndrome associated with an SMARCB1 mutation; hepatoblastoma should raise suspicion for familial adenomatous polyposis or BWS; patients with optic pathway tumors should be screened for NF1; 50% of patients with retinoblastoma have underlying germline RB1 mutations; there are multiple genes involved in germline CPS; for certain types of cancer, the majority of the cases have a germline mutation (eg, Sertoli-Leydig cell tumors [≈80%], pheochromocytoma and paraganglioma [≈70% have mutations in one of 5 genes]); however, in some conditions (eg, medulloblastoma, Wilms tumor) only a small percentage of patients have germline mutations

Major subgroups of CPS: categorized on the basis of pathogenesis, surveillance guidelines, and management; a paper from the American Association for Cancer Research (2016) subdivided CPS into several types (ie, Li-Fraumeni syndrome, multiple overgrowth syndromes, neurofibromatoses, neural tumor syndromes, gastrointestinal cancer syndromes, neuroendocrine syndromes, leukemia predisposition syndromes (an emerging area of interest), DNA instability syndromes (present heterogeneously because there are multiple genes involved in DNA repair pathways; all increase risk for cancer), and miscellaneous disorders (eg, PTEN, DICER1, and Noonan syndromes)

National Cancer Institute management guidelines: the pediatric oncologic series was published in 2017; guidelines based on a national consensus for patients <18 yr old were formulated for different types of CPS; recommended as a useful reference for clinicians providing care for patients with CPS

Pediatric Cancer Predisposition Program at Cleveland Clinic: a joint program of the Center for Personalized Genetic Health Care and the Department of Pediatric Hematology and Oncology; the clinical mission is to offer comprehensive genetic evaluation and cancer surveillance to individuals with known CPS or familial cancers; the research mission is to create a prospective clinical registry and biorepository of individuals with known or unknown CPS or familial cancers, and identify novel predisposition genes; the clinical team consists of cancer geneticists, oncologists, cancer genetic counselors, psychologists, social workers, and a nurse coordinator; patients must be referred to the clinic;, most referrals are made by pediatric hematology and oncology clinics, others come from cancer survivorship clinics, adult hematologists and oncologists, and community referrals

Future directions: more genes will be discovered as tumor profiling continues; researchers are attempting to improve genotype-phenotype correlations for specific CPS; personalized risk assessment and cancer surveillance guidelines are being developed for specific mutations responsible for CPS; novel surveillance tests (eg, tumor biomarkers, circulating tumor DNA) may increase noninvasive screening capabilities; prevention strategies being investigated for patients at high risk include chemoprophylaxis and dietary changes; there is need for research into the psychological impact of CPS; as the evidence base grows, the accuracy of surveillance guidelines and access to screening should improve

Readings

Brodeur GM, Nichols KE, Plon SE, et al. Pediatric cancer predisposition and surveillance: an overview, and a tribute to Alfred G. Knudson Jr. Clin Cancer Res. 2017;23(11):e1-e5. doi:10.1158/1078-0432.CCR-17-0702; Calissendorff J, Juhlin CC, Bancos I, Falhammar H. Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance. Cancers (Basel). 2022;14(4):917. Published 2022 Feb 12. doi:10.3390/cancers14040917; Florian AC, Woodley CM, Wang J, et al. Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells. NAR Cancer. 2022;4(1):zcac007. Published 2022 Mar 3. doi:10.1093/narcan/zcac007; Harris MH, DuBois SG, Glade Bender JL, et al. Multicenter feasibility study of tumor molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors: the individualized cancer therapy (iCat) study. JAMA Oncol. 2016; 2(5):608-615. doi:10.1001/jamaoncol.2015.5689; Kattner P, Strobel H, Khoshnevis N, et al. Compare and contrast: pediatric cancer versus adult malignancies. Cancer Metastasis Rev. 2019; 38(4):673-682. doi:10.1007/s10555-019-09836-y; Mody RJ, Wu YM, Lonigro RJ, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA. 2015; 314(9):913-925. doi:10.1001/jama.2015.10080; Parsons DW, Roy A, Yang Y, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2016; 2(5):616-624. doi:10.1001/jamaoncol.2015.5699; Porter CC, Druley TE, Erez A, et al. Recommendations for surveillance for children with leukemia-predisposing conditions. Clin Cancer Res. 2017; 23(11):e14-e22. doi:10.1158/1078-0432.CCR-17-0428; Walsh MF, Chang VY, Kohlmann WK, et al. Recommendations for childhood cancer screening and surveillance in DNA repair disorders. Clin Cancer Res. 2017; 23(11):e23-e31. doi:10.1158/1078-0432.CCR-17-0465; Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015; 373(24):2336-2346. doi:10.1056/NEJMoa1508054.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Lesmana was recorded at The 8th Annual Genetics Education Symposium – Genetics & Genomics: Applications for the Prevention, Detection and Treatment of Cancer, held virtually on September 30, 2021, and presented by Taussig Cancer Center, Cleveland Clinic, Cleveland, OH. For information on upcoming CME activities from this presenter, please visit clevelandclinicmeded.com. Audio Digest thanks the speakers and Taussig Cancer Center, Cleveland Clinic, for their cooperation in the production of this program.

CME/CE INFO

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The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

ON130701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.