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.