Discussion
This study outlines an approach to investigating familial cancer within a pediatric oncology unit from October 2019 to April 2022. Before initiating this project, only patients with a substantial family history or highly distinctive phenotypes were subject to investigation. The primary change implemented in the study was the establishment of a dedicated appointment for familial cancer assessment.
Based on the results found, our study revealed that 24% of the patients demonstrated a shift in their eligibility for genetic testing when assessed at a later stage in the oncological process. This leads us to recommend scheduling a dedicated appointment for the assessment of CPS in pediatric cancer patients, considering that all the necessary data may not be available at the time of diagnosis.
The most common reason for changes in the criteria ”pre-data” vs ”post-data” is the physical examination and family history. This discrepancy may occur because certain phenotypic features were not initially observed at diagnosis or because the patient underwent physical changes that were not apparent during the initial examination. A similar situation arises with family history. In some cases, family history data was inaccurately reported by the families at the time of diagnosis, or new family members may be subsequently diagnosed with cancer during the patient’s follow-up. The study of CPS should also be dynamic, and patients who initially do not meet the criteria should be re-evaluated as new family data becomes available.
In terms of the percentage of patients in whom a pathogenic or likely pathogenic variant has been identified, our study revealed such variants in 6% of patients in our cohort. This percentage is lower than reported in the literature1-5, most likely attributed to excluding of patients with specific phenotypes.
Screening all children with cancer is of significant research interest, however it is accompanied by the trade-off of the cost and reduced chances of identifying pathogenic variants in patients who do not meet any risk criteria. This, in turn, presents challenges in managing the uncertainty associated with VUS. In the context of our research, we have observed that it is prudent to exclude patients with a strong suspicion of a particular syndrome. Conducting a WES in such cases may be unnecessary, as they can be studied more selectively. Moreover, these selective studies tend to be more cost-effective and are typically covered by the patient’s insurance. For the remaining patients, we have implemented clinical screening, which considers factors such as family history, physical characteristics, and, most importantly, the type of tumor. The type of tumor has been shown to be the most influential factor in detecting CPS.
Selecting patients by a clinical screening aligns with existing literature, notable supported by the 2022 review conducted by Rossini et al17, which discusses various strategies for studying familial cancer in pediatrics. The authors concluded that the most efficient approach is to study patients selected using any of the clinical tools described10,13,14,17.
In terms of determining the most effective genetic approach, whether WES, trio-WES, a multigene panel, or single gene analysis, there are limited studies available for comparing their advantages and specific indications8.
The clinical approach is crucial, and if a specific syndrome is suspected, a single gene analysis is the preferred option. We recommend a multigene panel for clinical use due to its comprehensive gene coverage and targeted information retrieval. WES and whole genome sequencing should be reserved for research purposes, patients with unclear cancer or multisystem phenotypes, and those with negative or inconclusive results from previous single-gene or multigene testing. Certainly, if resources are available, the most comprehensive information can be obtained through WES, ideally complemented by pairing the results with tumor sequencing.
There is some controversy regarding the detection of mutations in genes associated with the development of cancer in adulthood. In the study by Sylvester et al5, which compiles the results from six different cohorts of pediatric patients investigated for the presence of CPS, various approaches are employed. In all cases, genes related to adult-onset cancer, such as BRCA2, MSH2 and MSH6, are examined. In the combined analysis of the 6 cohorts, 0.4% of patients were found to carry pathogenic or likely pathogenic variants in BRCA1 and 0.5% in BRCA25. The tumors most frequently associated included medulloblastoma, neuroblastoma (as in the case of our patient), and acute lymphoblastic leukemia. Concurrently with the identification of BRCA2 in our patient, a 30-year-old maternal aunt, that had not been previously referred to genetic testing, was diagnosed with breast cancer. Cascade testing was then performed, and the mutation was identified in the mother, who was informed of the results, leading to the entire family to undergo genetic counseling.
We advocate for a collaborative approach to the study of CPS, involving pediatric oncologists and geneticists. The continuity of care through regular check-ups in pediatric cancer patients, allows for timely updates on any occurrences of new tumors in the family. Geneticists are crucial in guiding the approach to cancer predisposition studies and interpreting genetic tests. Genetic counseling and the long-term follow-up of patients and their families with CPS should be a collaborative effort involving pediatric oncologists, geneticists, and adult oncologists.