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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pediatric Cancer; Congenital Anomaly
• Intervention / Treatment: Other: Whole Genome Sequencing; Other: Questionnaire Administration; Other: Biospecimen collection; Other: Laboratory Biomarker Analysis

Detailed Description

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").

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/ Dan L Duncan Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

GOBACK; 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; Saliva collection and request for banked blood and tumor samples for sequencing; Other: Questionnaire Administration; Study questionnaire will include modules that collect information on maternal reproductive history, exposure to known teratogens, medical history, and previous genetic testing.; Other: Biospecimen collection; Saliva collection and request for banked blood and tumor samples for sequencing and biomarker analysis; Other: Laboratory Biomarker Analysis; Saliva collection and request for banked blood and tumor samples for biomarker analysis

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2021
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: September 28, 2021
• First Posted (Actual): October 8, 2021

Study Record Updates

• Last Update Posted (Actual): February 6, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Congenital Anomaly
• Additional Relevant MeSH Terms: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Congenital Abnormalities; Neoplasms; Investigative Techniques; Genetic Techniques; Sequence Analysis; Sequence Analysis, DNA; Whole Genome Sequencing
• Other Study ID Numbers: AEPI19N1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No