Update on Genetic Counselor Practice and Recommendations for Pediatric Cancer Predisposition Evaluation and Surveillance

In recent years, significant advancements in pediatric cancer genetics including the identification of novel cancer predisposition genes, clinical use of tumor genetic testing, and phenotypic expansion of cancer predisposition syndromes (CPS) have increased indications for genetic counseling and germline testing. Tumor genetic testing with or without a germline sample is also increasingly integrated at diagnosis, resulting in a need for adaptive genetic counseling models. Differences in practices and resources between centers in and outside the United States impact how germline genetic testing is incorporated into care and the outcomes for patients and families. Additionally, social determinants of health impact the ability of patients and families to access equitable care.

The 2017 AACR genetic counseling paper provides a more in-depth review of genetic counseling, testing processes, and test selection recommendations that largely remain relevant to today’s practice (1). In this article, we discuss additional perspectives on advances in the field since then. See Table 1 for key takeaways and recommendations.

Traditionally, children with cancer were referred for genetic counseling and testing if a clinician identified a personal and/or family history suggestive of a CPS (1–3). Referral indications specific to each tumor type are discussed within the tumor and syndrome specific papers in this AACR series and in the literature (3–5). Family history remains a very useful criterion, but is negative in 40% to 60% of pediatric patients with a CPS (6–9). Thus, requiring positive family history as a referral indication will miss children with CPS and can also create health disparities as individuals from historically excluded communities may have less accurate family health history information (10, 11).

To aid in the identification of children who warrant cancer genetic counseling and/or testing, referral guidelines (5, 12) and more recently an eHealth decision support tool called MIPOGG (McGill Interactive Pediatric OncoGenetic Guidelines; ref. 13) were developed and studied internationally using retrospective cohorts. These resources were effective at identifying children with the highest likelihood of having a CPS (13–15) and can help to narrow down a population for testing, especially in resource-limited clinics. However, resources that restrict testing criteria will miss children with CPS, especially if they are not updated periodically to keep pace with growing knowledge (16).

Efforts to expand access to germline genetic testing are underway. Universal testing of children with cancer is being considered or, in some settings, is already in practice to increase the identification of a CPS. Such testing lessens the onus on the oncology provider to identify and successfully refer all at-risk patients. Removing these barriers contributes to equitable access to these services. However, to move toward universal testing, new workflows are needed for education, consent, and return of results.

Testing for and identification of CPS also occurs in children who do not have cancer, including children with physical findings associated with CPS, as well as those at familial risk for a pathogenic/likely pathogenic variant (PV/LPV) in a CPS gene (1). In addition, unexpected PV/LPVs in CPS genes may be identified as secondary findings on clinical exome or genome sequencing (ES/GS) ordered for non-oncologic indications (17–19). Finally, genomic newborn screening (gNBS) is being studied across the world and is potentially on the horizon for CPS (20, 21).

Referral timepoints for genetic counseling may differ depending on the genetic testing model used (see “Genetic Counseling Models Evolve”). Genetic counseling before genetic testing can provide families an opportunity to discuss benefits and potential downsides of testing for their child and family, make an informed decision about timing and amount of testing, and increase preparedness to cope with the outcomes (22, 23). Even if not seen by a genetic counselor, genetic testing should ideally be offered within 1 to 2 months of diagnosis to avoid delaying or missing a CPS diagnosis. For children with hematologic malignancies, if germline genetic testing is indicated, it is necessary to obtain a sample that does not include dysplastic blood cells. We recommend obtaining a skin biopsy at the time of bone marrow biopsy or other surgical procedure, which allows for germline testing to be completed in a timely manner if the results may alter treatment or donor selection for bone marrow transplant. If germline results are not time-sensitive, a blood sample at the time of remission can be used. Some prefer skin biopsy for all myeloid malignancies, even if the patient is in remission. Saliva or buccal swab samples are not recommended for patients who have an active hematologic malignancy, as the DNA from these samples is primarily extracted from leukocytes (Table 2). Families who decline genetic testing at this timepoint, should be offered the option for testing again in the future. If the child is at the end of life or testing is not possible, DNA banking should be offered whenever feasible.

Children undergoing active treatment and individuals followed in survivorship clinics may be candidates for first time or updated genetic evaluations as testing practices and technologies evolve and as children and adolescents and young adults (AYA) reach different developmental stages. We also encourage families to contact a cancer genetics professional at least every 5 years, and/or when: personal or family histories change, in remission as they transition from cancer treatment to CPS surveillance (23), transitioning to adult care, or planning a family to provide updates on testing options, interpretation of previous results and surveillance recommendations.

The ability to detect somatic and germline variants is improving with newer testing methods such as advanced next-generation sequencing techniques, long-read sequencing, and RNA sequencing (8, 16, 24, 25). Testing practices vary by institution and provider; however, advancements bring new considerations for implementation (26–29).

Genetic testing is performed on tumor samples for diagnostic, prognostic, and treatment purposes. The terms “somatic” and “tumor” testing are often used interchangeably; however, there are important differences that directly impact interpretation of the reports generated. “Somatic” refers to genetic variants that are present only in the tumor and not in the germline. To obtain somatic variants, germline variants must be removed or “subtracted” from the tumor variants. “Tumor” (also known as “tumor-only”) testing refers to genetic variants present in the tumor, which may include variants of both somatic and germline origin. Thus, tests and reports may be tumor-only (somatic and germline variants are not differentiated), tumor with germline subtraction (somatic), or paired tumor-germline with reporting of somatic and germline variants (30).

These tests are available through research as well as clinical care (6, 7, 9, 31, 32). When choosing which test to order and evaluating the results, it is important to understand the methodology, sample(s) (i.e., tumor ± germline), advantages, and limitations of the test (Tables 2 and 3). In addition, gene content, gene coverage, analytic pipelines, variant interpretation, and reporting practices (particularly if any germline PV/LPV are included and identified as such on somatic reports) vary significantly among somatic and germline tests, as well as among laboratories (30). Despite their differences, these tests can identify PV/LPVs in genes associated with CPS and thereby prompt genetic counseling and germline confirmation. Pretest consent for tumor testing that includes reporting of germline variants should discuss the possibility of identifying such variants, and if applicable, the potential to identify adult-only cancer risks (30, 33, 34). Importantly, clinically relevant germline variants may not be identified or reported on tumor-only, somatic, or paired tumor-germline test reports for various reasons (27, 35). Therefore, genetic counseling and germline testing should be offered when there is clinical suspicion for a CPS, even in the absence of suspected or confirmed germline variants on tumor testing.

Germline testing approaches for CPS in children with cancer are moving toward the use of broad multigene panels, similar to approaches in adult cancer genetics clinics (2). As knowledge improves regarding the expanded associations between specific tumor types and genes, as well as specific genes and broader tumor types, it can be challenging to stay up-to-date and choose the best test for each patient. Broad gene panel testing reduces the likelihood of missing an identifiable CPS in a child, especially when clinics are implementing universal genetic testing. However, broad testing can also identify PV/LPVs in genes which may not have clear penetrance estimates, surveillance guidelines and/or association with the patient’s cancer type (or in some cases, with any pediatric cancers), potentially complicating management recommendations. In addition, broad testing leads to more variants of uncertain significance (VUS) compounded by a higher rate of VUS in minority racial and ethnic populations due to lack of inclusion in genetic research data (36–38). Variant Curation Expert Panels have been formed through U.S.-based Clinical Genome Resource (ClinGen) to help address variant classification challenges; however, many VUS are unable to be reclassified and currently there are no clear guidelines to address reduced penetrance alleles (39). Understanding such inconclusive results may be more challenging, stressful, and/or unwanted for some providers, patients, and families than others.

Cascade testing should be offered for first-degree relatives of a child with a CPS. When the CPS gene has limited data regarding cancer risks, penetrance, and surveillance, it is important to discuss the limitations of our understanding and the pros/cons of testing with the family, to facilitate a joint decision about testing, as well as long-term follow up (23).

As broad scope tumor and germline testing becomes integrated into clinical care of children with cancer, so does the potential to identify PV/LPVs in genes considered to be clinically actionable in adulthood and for which the pediatric cancer risks and surveillance are poorly understood. These are sometimes heterozygous variants in genes for which there is also an autosomal recessive multisystem condition with increased cancer risks in childhood, such as BRCA2 or PMS2.

The presence of such germline PV/LPVs in a child with cancer should prompt referrals for genetic counseling and cascade testing. The most immediate at-risk individual with respect to cancer development is oftentimes the parent(s) from whom the child inherited the variant. In addition, reproductive options may be impacted for parents in the process of family planning. Post-test counseling should emphasize the importance of follow up genetic counseling as the patient ages and the cancer risks and management become more relevant.

Whether and when to test children who do not have cancer for these variants are nuanced decisions impacted by multiple factors. Testing children for adult-onset cancer risk historically has been recommended against (40, 41). However, these recommendations are written from a cultural and ethical framework that does not take diverse family perspectives and needs into full consideration.

Generally, we recommend reserving testing for adult-onset cancer risk variants in unaffected children to the age of legal consent (which can vary by state or country), especially when no medical intervention or surveillance is recommended in childhood. The decision to test earlier may be influenced by other factors including family interests, values, preferences (42–44), social situations, and/or specific clinical considerations. Examples of clinical scenarios that may influence the decision to test a child include evidence of the variant’s role in a sibling’s pediatric tumor formation, concern for features of an associated recessive condition, consideration of the minor as a bone marrow transplant family donor (45, 46), and use of genetic results to guide gender-affirming care decisions in a transgender minor (47, 48).

Readers are encouraged to review the more in-depth article on this topic in the current 2024 AACR Pediatric Cancer series (49).

Historically, genetic counseling models included a genetic counseling visit prior to genetic testing. The intent of pretest genetic counseling is to provide information about the likelihood of identifying a CPS in the patient, the potential implications of a CPS on personal and family members’ cancer risks, insurance concerns, possible psychosocial sequela, and to facilitate informed decision making and consent with or without patients’ assent (50).

As previously noted, tumor and germline genetic testing are increasingly ordered by non-genetics providers at diagnosis with the intent to plan treatment and predict outcomes (38, 51–54). Genetic testing coordinated during routine oncology care, often with support from genetic counselors and/or other genetic specialists, automated tools, or education materials, but without formal pretest genetic counseling has been termed point-of-care (POC) genetic testing. This model has been widely adopted and studied in adult oncology and has increased uptake of and reduced disparities in access to genetic testing (55–60). Little is known about the use or effectiveness of this approach in pediatric oncology but exploration of POC genetic testing for children with cancer is warranted.

When genetic testing is performed without pretest genetic counseling, we strongly recommend post-test genetic counseling to interpret the results in context of personal and family history, especially when testing identifies a CPS, a VUS, or is negative but the patient’s history or family history is strongly suggestive of a CPS (2, 22). Access to appropriate post-test genetic counseling and support and management services are required for families to effectively understand and use this information (61).

Clinical guidelines and uniform insurance coverage for the clinical use of broad multigene panels or ES/GS in the tumor and germline in pediatric oncology are lacking, despite multiple studies revealing that somatic and germline findings impact clinical care in a significant proportion of patients (6, 7, 9, 16, 62, 63). This limits the number of children with cancer who are identified as high risk and are offered testing and further limits the number of patients able to complete testing due to cost.

Some health insurances cover genetic testing but policies differ by plan and location. Health insurance coverage of genetic testing for germline and somatic purposes should be addressed separately by coverage policies and supported for children with or at-risk for cancer. For equitable access, healthcare systems should also recognize the importance of testing coverage in both inpatient and outpatient settings. For cascade testing, access to testing and subsequent surveillance is particularly challenging for uninsured relatives (23). Many U.S. commercial laboratories offer options to mitigate some of these challenges, including pre-authorization services, remote sample collection via testing kits or mobile phlebotomy services, free familial variant testing, and financial assistance programs. However, the sustainability of such programs is unclear. These barriers disproportionately impact those who have lower knowledge or awareness of genetic counseling and genetic testing, or harbor greater mistrust of the medical community due to a history of medical racism and discrimination in their communities (64, 65).

Insurance and health system cost-coverage, as well as access to centers offering cancer predisposition surveillance, also present major barriers to tumor surveillance for many families at high risk for cancer (23). As studies continue to demonstrate the efficacy of surveillance protocols for pediatric CPS in reducing morbidity and mortality, emerging evidence suggests that some surveillance protocols are also cost-effective (66, 67). Additionally, surveillance may be necessary for emotional and physical well-being with the benefits outweighing the drawbacks (68).

Parents of children with cancer who had genetic testing at the time of diagnosis reported being glad to have the information but the timing was overwhelming (69). Parents of children with CPS experience distress; however, they also report benefits to knowing this diagnosis such as being able to prepare for the future (69–72). Ultimately the diagnosis of a CPS presents new information with additional benefits and challenges for families.

Psychosocial issues related to pediatric cancer surveillance can be complex, with changing considerations and needs that unfold from the time of genetic diagnosis through the AYA period. The previous CCR Pediatric Oncology genetic counselor recommendations (1) outline the importance of balancing the evidence and effectiveness of surveillance with the psychosocial burdens and benefits they may confer on patients and families.

An important update to the literature has focused on the psychosocial impact of cancer surveillance in adolescents with CPS. Themes from one study with semi-structured interviews with parents and adolescents included benefits of surveillance, challenges of surveillance, factors influencing the surveillance experience, and positive factors that help families manage their surveillance-related worries and lived experiences with a CPS. For example, for individuals with Li-Fraumeni syndrome, clinic visits every 3 months cause school absences and are reminders of cancer risks. However, the passage of time and adjusting one’s state of mind were both positive factors that helped families cope with lifelong surveillance. Many considerations and recommendations for health care providers were presented, most notably, the potential benefit for additional psychological support embedded in the surveillance clinic, particularly in the first year of surveillance (73). We therefore recommend having psychosocial providers such as psychologists and social workers embedded in cancer predisposition clinics. As surveillance is lifelong, non-genetic healthcare providers should also be made aware of the burdens and benefits of surveillance and risk management. This can help improve the care of young people with CPS and their families (74).

As more children survive cancer and more CPS are diagnosed via expanded testing, the importance of repeat genetic counseling and preparedness for transition to adult cancer surveillance care cannot be understated. Among patients with AYA cancer with CPS, some do not recall their genetic test result, confuse follow-up imaging for their cancer diagnosis with cancer predisposition surveillance, and/or hold misperceptions about cancer risks or screening for their CPS (23, 72). In addition, AYA may not understand their reproductive options and/or their at-risk children may not get the appropriate surveillance, without repeat genetic counseling. These as well as findings from transition studies for AYA with CPS or other chronic conditions (75–77) argue for robust transition programing for AYA with CPS to realize the potential benefits of surveillance into adulthood.

More frequent use of genetic testing in pediatric oncology, along with the application of advanced testing methods, holds great promise for identifying patients with CPS as well as detecting somatic variants that inform diagnosis, prognosis, and treatment. Continued research is needed to identify the informational and support needs of parents of children diagnosed with cancer and to develop tools and genetic counseling models to address these. Equitable access to genetic counseling and testing is vital to ensure that patients with pediatric cancer, children with a CPS, and at-risk family members receive appropriate cancer surveillance, preventive or risk-reducing medical management, and psychosocial support.

W.K. Kohlmann reports other support from Veterans Health Administration during the conduct of the study. No potential conflicts of interest were disclosed by the other authors. 

We would like to thank Chieko Tamura from the FMC Tokyo Clinic, Tokyo, Japan, for her contributions during the 2023 AACR Childhood Cancer Predisposition Workshop and Zachary Gallinger and Irina Seredyuk for their assistance with the formatting of the tables.