Investigating How Childhood Tumours and Congenital Disease Develop

Every cell and every organ in the human body derives from a fertilised egg. As the fertilised egg divides, a human being develops and grows. The process of how the fertilised egg divides and forms a human being is very sophisticated and is directed by the genetic information, the DNA, that is present in every cell.

When errors, mutations, in the DNA code arise, the orderly process of human development can be disrupted. This can lead to the development of tumours during childhood and congenital diseases (that is, abnormalities that children are born with).

The aim of this study is to define exactly which DNA errors underpin childhood tumours and congenital diseases.

Study Overview

• Status: Enrolling by invitation
• Conditions: Congenital Disorders; Childhood Tumor

Detailed Description

Cancers and some congenital anomalies are caused by changes (mutations) in the genetic code (DNA) of cells. The use of Next Generation Sequencing (NGS) has enabled the study of the genetic changes that underpin these diseases, genome wide and at base pair resolution.

A key question about the molecular pathogenesis of a range of childhood tumours and congenital anomalies that remains unanswered is the order in which the different mutations arise. To define the order in which mutations arise, the investigators will need to reconstruct the life history of individual tumours / anomalies. This can be achieved by segregating the major clone ('ancestral' cell) from sub-clones or by studying multiple areas from the same lesion. Although this approach allows timing of mutations to some degree, in childhood tumours and congenital lesions this approach is fundamentally limited by the inability to define embryonic mutations. The basis of the limitation is that the lesions in question is conventionally compared to the patient's germline (the genetic information they have from birth). In such a comparison embryonic mutations will be misclassified as either germline or somatic (acquired).

To overcome this limitation one would have to compare the lesion to the parental germline.

Thus, here this study proposes to perform the first NGS study of childhood tumours and congenital anomalies, focusing on defining the embryonic pathogenesis. A unique feature of this study will be that lesions will be compared to the parental germline to define embryonic mutations. A focus of the analysis will be to define order in which mutations arise.

• Study Type: Observational
• Enrollment (Estimated): 600

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Participants will have either a tumour or congenital anomaly. The investigators aim to also recruit the participant's biological parents. In some cases, the participant's sibling(s) and close relatives may also be recruited into the study. Where post-mortem material will be accessed, the participant will have been enrolled in the study whilst alive.

Potential participants will be identified by participating NHS clinicians on an ongoing basis and from registers of patients internal to each participating NHS unit.

Surplus samples will be identified by participating NHS clinicians. Some samples may also be obtained through Biobanks.

Description

Inclusion Criteria:

• Presence of childhood tumour / congenital disease, or relative of participant with childhood tumour / congenital disease
• Sufficient 'surplus to diagnostic/clinical use' tissue is available
• Child assent and parental/guardian consent obtained where applicable

Exclusion Criteria:

• Insufficient surplus tissue is available

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Description of the genetic mutations of each tumour and congenital anomaly.	For each tumour a catalogue of mutations will be derived from sequencing reads. The catalogues will be compared across tumour types / anomalies to identify the mutations that drive individual tumour types / anomalies. The life history of each tumour / anomaly will be determined. Methylation data will be analysed to derive a methylation profile for each tumour. The profiles of individual tumours will then be compared with each other to see whether tumour-type specific methylation profiles exist.	9.5 years

Collaborators and Investigators

• Sponsor: The Wellcome Sanger Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2017
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: July 4, 2024
• First Submitted That Met QC Criteria: September 2, 2024
• First Posted (Estimated): September 5, 2024

Study Record Updates

• Last Update Posted (Estimated): September 5, 2024
• Last Update Submitted That Met QC Criteria: September 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 207523

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: As is customary in the field, we will publish our anonymised data in research databases and archives. This includes EGA (European Genome-phenome Archive) where data will be made accessible via managed access to researchers or companies worldwide.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No