Genetic Overlap Between Anomalies and Cancer in Kids in the Children's Oncology Group: The COG GOBACK Study

Study Overview
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Brief Summary
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One of the strongest risk factors for cancer in children and adolescents is being born with a congenital anomaly. In fact, data from registry linkage studies imply that 10-15% of childhood cancer risk could be attributable to having a congenital anomaly. As an estimated 10 million children worldwide are born with a congenital anomaly per year, the public health implications of identifying why some of these children develop cancer are thus substantial. While these studies have been informative, registry data alone offers no possibility of molecular or sequencing studies to identify the specific genetic basis underlying the co-occurrence of anomalies and cancer susceptibility. Therefore, the investigators developed the first phase of the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study to address these limitations. Using data from birth defects and cancer registries from four states, the investigators identified numerous novel specific anomaly-cancer associations. In the GOBACK Study the investigators identified an increase in cancer risk among children with any chromosomal abnormality and any non-chromosomal birth defect. Additionally, children with congenital anomalies developed a variety of cancers, therefore the investigators propose to evaluate a range of cancers among children with congenital anomalies. By pooling registry data across four states in the GOBACK Study, the investigators found that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. Notably several of these congenital anomalies are not characteristic of known cancer predisposition syndromes. Therefore, our preliminary studies lay the framework for this application. The objectives of the current study are to (1) interrogate the genomes of children with co-occurring non-chromosomal congenital anomalies and cancer enrolled in Project:EveryChild to identify genetic features associated with these combined phenotypes, and (2) verify congenital anomalies and determine the phenotypic spectrum among children with cancer enrolled in Project:EveryChild with self-reported congenital anomalies (deep phenotyping). For this study the investigators will utilize Project:EveryChild to identify, contact, and enroll case-parent trios for children with co-occurring non-chromosomal congenital anomalies and cancers. From each enrolled family the investigators e will collect DNA from the affected case and one or both biological parents to comprise each case-parent trio. The investigators will include siblings if available. The investigators will also characterize case-parent trios based on demographic and clinical characteristics utilizing information collected via self-administered questionnaires and medical records. Ultimately the findings from this study could lead to 1) determining the potential genetic mechanisms that underlie these co-occurring conditions; 2) improving cancer risk-management strategies among children with birth defects; and 3) identifying the role congenital anomalies play in outcomes and survivorship among children diagnosed with cancer.

Detailed Description
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OBJECTIVES: 1.1 Primary Aim Interrogate the genomes of children with co-occurring non-chromosomal congenital anomalies and cancer enrolled in Project:EveryChild to identify genetic features associated with these combined phenotypes. 1.2 Secondary Aim Verify congenital anomalies and determine the phenotypic spectrum among children with cancer enrolled in Project:EveryChild with self-reported congenital anomalies (deep phenotyping).

Official Title
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Genetic Overlap Between Anomalies and Cancer in Kids in the Children's Oncology Group: The COG GOBACK Study

Conditions
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Congenital Anomaly, Pediatric Cancer

Intervention / Treatment
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* Other: Whole Genome Sequencing
* Other: Questionnaire Administration
* Other: Biospecimen collection
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must have been diagnosed with cancer at ≤25 years of age and have been diagnosed with one or more congenital anomalies reported through the APEC14B1 registry intake data. All types of non-syndromic birth defects and all types of cancers are eligible, regardless of patient vital status. The patient must be enrolled on APEC14B1 with consent to future contact and registered with COG by a North American member institution. Note: (history of) treatment on a COG therapeutic trial is not required. Language: English, French, or Spanish speaking. The patient may participate regardless of the availability of biological parent(s). Exclusion Criteria: Patients with a self-reported genetic syndrome as identified in the APEC14B1 Registry are not eligible.

Ages Eligible for Study
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Minimum Age: 0 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| GOBACK<br>The patient must have been diagnosed with cancer at ≤25 years of age and have been diagnosed with one or more congenital anomalies reported through the APEC14B1 registry intake data. For all patients in APEC14B1 with self-reported congenital anomalies the investigators will: 1) recruit cases; 2) administer the GOBACK Study questionnaire; 3) collect biological samples for sequencing; and 4) obtain medical records to verify anomalies. Medical records will be used to validate self-reported congenital anomalies and is a crucial step prior to sequencing. Additionally, the investigators will be able to identify those with well-established cancer predisposition syndromes that involve congenital anomalies, such as WAGR syndrome. | Other: Whole Genome Sequencing<br>* Saliva collection and request for banked blood and tumor samples for sequencing<br>Other: Questionnaire Administration<br>* Study questionnaire will include modules that collect information on maternal reproductive history, exposure to known teratogens, medical history, and previous genetic testing.<br>Other: Biospecimen collection<br>* Saliva collection and request for banked blood and tumor samples for sequencing and biomarker analysis<br>Other: Laboratory Biomarker Analysis<br>* Saliva collection and request for banked blood and tumor samples for biomarker analysis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interrogate the genomes of children with co-occurring non-chromosomal congenital anomalies and cancer enrolled in Project:EveryChild to identify genetic features associated with these combined phenotypes. | Analyze de novo single-nucleotide variants (SNVs), copy number variants (CNVs), and insertions/deletions (INDELs) obtained through whole-genome sequencing of co-occurring non-chromosomal congenital anomalies and cancer case-parent trios, which are necessary to identify genes with de novo mutations. The investigators plan to enroll a maximum of 1,000 case-parent trios. For individuals on COG therapeutic studies, no treatment outcomes would be requested or reported as part of this study. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verify congenital anomalies and determine the phenotypic spectrum among children with cancer enrolled in Project:EveryChild with self-reported congenital anomalies (deep phenotyping). | The primary analyses of data generated in this secondary aim will be descriptive in nature. The objective will largely be to verify congenital anomalies and determine the phenotypic spectrum of children with congenital anomalies and cancer. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Anomaly