To evaluate the performance of a *genotype first approach* (WES-based panel analysis) in diagnostics of genetic predisposition in children with cancer or neoplasms, compared to the current *phenotype first approach* (standard of care). In particular…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pediatric cancer predisposition syndromes diagnoses (molecular and/or
clinical). We will compare the number of cancer predisposition syndromes
diagnosed by the genotype first approach (molecular diagnosis based on WES
panel analysis) to the phenotype first approach (clinical diagnosis and/or
molecular diagnosis based on targeted tests).
Secondary outcome
We will evaluate the number of pediatric CPSs diagnosed by the genotype first
approach and the phenotype first approach for different groups of tumor types.
Other secondary study parameters are:
- The number of patients referred to a clinical geneticists
- The number of children who already have a molecular confirmed cancer
predisposition syndrome at the time of cancer/neoplasm diagnosis.
- The total number of pediatric cancer predisposition syndromes
- The number of variants of unknown significance (VUSs) detected by WES panel
analysis.
- The number of children with hematological malignancies who have an underlying
PID or IBMFS as cancer predisposition syndrome
- The performance of the decision-support questionnaire (MIPOGG tool; standard
of care) (positive predictive value, negative predictive value, sensitivity and
specificity); The MIPOGG tool serves as a decision-support tool to help
streamline referrals to clinical genetics services and assists the pediatric
oncologist to assess whether a referral would be appropriate for the patient
- The number of children who refuse to participate in our study and the reasons
why children/parents refuse to participate
- The motivations and concerns of families who participate in our study
- The impact of participating in the study and receiving genetic test results
- The knowledge families have on genetic concepts
- How families made a decision on participating in the study and how they
experienced the counseling
Based on these endpoints we will develop guidelines for best strategy to detect
cancer predisposition syndromes in a routine clinical setting. Furthermore,
this study will contribute to improving the counseling and support offered to
future families.
Background summary
Recognition of genetic predisposition in children with cancer or neoplasms is
of high clinical significance since it might influence therapy choices,
surveillance policies and counseling of relatives. Cancer predisposition
syndromes (CPSs) can be suspected based on specific hallmarks such as a
positive family history or the presence of congenital anomalies. Due to the
expanding phenotypic diversity, the upfront *phenotype based* recognition of
CPSs is becoming more challenging for clinicians. Furthermore, next-generation
sequencing (NGS) studies have revealed mutations in pediatric cancer
predisposition genes in patients without any clinical features suggestive for
genetic predisposition. Additionally, patients with genetically-determined
defects in the production and/or function of (white) blood cells can have an
increased risk of hematological malignancies. These include inherited bone
marrow failure syndromes (IBMFS) and primary immunodeficiencies (PID), with
important genetic overlap between the two disease groups.
From previous research it is known that participating in NGS and receiving
genetic test results can be psychologically impactful. Little is known about
the experiences with NGS of parents and children in a pediatric oncology
setting
Study objective
To evaluate the performance of a *genotype first approach* (WES-based panel
analysis) in diagnostics of genetic predisposition in children with cancer or
neoplasms, compared to the current *phenotype first approach* (standard of
care). In particular we will focus on discrepancies in CPS diagnoses between
these two approaches. Furthermore, we will obtain insight into the prevalence
of germline mutations in PID- and IBMFS-associated genes in children with
hematological malignancies. In addition we will evaluate the psychosocial
aspects of participating in NGS in a childhood cancer setting to improve
counseling of future families.
Study design
Prospective nationwide cohort study. We will use WES-data generated routinely
from all children diagnosed with cancer or neoplasms in the Prinsess Máxima
Center. After informed consent, a panel of known pediatric cancer predisposing
genes will be analysed in the germline data. In the Hemato add-on study,
children with hematological malignancies will be additionally analysed for a
panel of potentially relevant PID- and IBMFS-associated genes (separate
informed consent requested retrospectively for already included patients, or
prospectively for newly recruited patients). In addition, patients > 12 yrs.
and parents who participate in NGS will be asked to complete questionnaires and
interviews (children >12yrs).
Study burden and risks
Burden and risks: the burden for patients is minimal since for most of them no
additional interventions are needed. In patients from whom a germline DNA
sample is not available, venipuncture will be combined with a puncture as part
of the cancer diagnostics/treatment. To minimize the chance of detecting
*unsolicited findings* WES data will be analysed using a gene-specific filter
of known pediatric cancer predisposing genes and a panel of potentially
relevant PID- and IBMFS-associated genes.
Benefit: knowledge of a cancer-predisposing mutation in a child can be
beneficial in terms of treatment choices, surveillance protocols, and genetic
counseling of family members.
Group relatedness: pediatric tumors are genetically and biologically different
form tumors in the adult population.
Burden of the psychosocial part of the study remains limited to the time needed
to complete questionnaires and/or interviews.
Heidelberglaan 25
Utrecht 3584 CS
NL
Heidelberglaan 25
Utrecht 3584 CS
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria for the main study PrediCT:
- Children (age < 19 years) newly diagnosed with cancer or neoplasms at the
Princess Máxima Center (in a period
of three years)
- Written informed consent (by patient when aged 16 years or older, by patient
and parent(s) when aged 12-16
years, by parent(s) when younger than 12 years)
Additional inclusion criteria for REFLECT:
- Consent for participation in PrediCT
- Written informed consent for REFLECT. This can include:
• Parents (of children 0-19 years)
• Children aged 12-16 years (additional consent by their parents needed)
• Children aged 16-19 years.
Additional inclusion criteria for the Hemato add-on study:
- Consent for participation in PrediCT
- Children (age < 19 years) diagnosed with hematological malignancies
(including myelodysplastic syndromes) at the Princess Máxima Center
- Written informed consent for the Hemato add-on study (by patient when aged 16
years or older, by patient and parent(s) when aged 12-16 years, by parent(s)
when younger than 12 years).
Exclusion criteria
Children and/or their parents who don't want to know the results of the DNA
test (pediatric cancer gene panel
analysis).
Additional exclusion criterion for REFLECT: Insufficient proficiency in Dutch.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL70480.041.20 |
| Other | Trial NL8456 |