Predisposition, GeneticNCT06584994
Investigating the Role of Genetics in Disease Predisposition
An observational study of Predisposition, Genetic and Cancer, run by The Wellcome Sanger Institute at 1 site in United Kingdom.
Trial summary
Gametogenesis is the production of sperm and eggs; it takes place through the process of meiosis. Gametogenesis is subject to the acquisition of mutations as with other processes in the body. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Predisposition, Genetic, Cancer, Mutation
- What is being tested?
- sample collection
- How many people
- 1,000 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 20 Jun 2021to 1 Mar 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Children diagnosed with disease predisposition syndromes and/or cancer and their family members (mother, father, siblings) We may also include the wider family (maternal/paternal aunts, uncles and grandparents) Recruitment and the sequencing of both prospectively collected samples and those retrospectively collected from tissue banks will run for the first four years of the study.
Who may be able to join
- Minimum of child affected with cancer pre-disposition syndromes and their father
- Additional family members of consented father and child duos (Mother, same parent siblings, Maternal/Paternal Aunts, uncles and grandparents of affected child)
- Reproductive tissue samples from both men and women affected by cancer collected with consent for use in research.
- Reproductive tissue samples from both men and women unaffected by cancer collected with consent for use in research.
Who cannot join
- Fathers who do not wish to donate a semen sample or are unable to will be excluded from the study, as will their families
- Fathers who have had a vasectomy will be excluded from the study as will their families
- Adults who do not have the capacity to consent for themselves will be excluded from the study.
- Families in which both parents do not have capacity to consent will also be excluded as they will be unable to give parental consent for their children's participation.
- In order to be eligible siblings must share the same two parents as the affected child, all other siblings will be excluded from the study.
- Male relatives in the extended family (Maternal/Paternal Aunts, uncles and grandparents of affected child) unwilling or unable to donate both a blood or saliva sample and a semen sample will be excluded from the study.
- Participants who do not have a good understanding of the English language will be excluded from the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Investigating Clonal Dynamics in Gonads and Their Role in Disease Predisposition
Gametogenesis is the production of sperm and eggs; it takes place through the process of meiosis. Gametogenesis is subject to the acquisition of mutations as with other processes in the body. Many of these mutations are somatic, meaning that they occur during life as part of the process of cell division rather than being passed down from parents. When somatic mutations take place during gametogenesis, there is the potential for hereditary genetic consequences. However, the processes that cause the mutations during gametogenesis and the implications they have for heritability and disease predisposition are poorly understood.
The goal of this research is to provide a detailed description of the genetic changes in gonadal tissues, and to understand how mutations acquired during the production of germ cells (sperm and eggs) contribute to the predisposition to a wide range of rare diseases and cancer predisposition in future offspring.
Read the detailed description
Predisposition to rare disorders and cancers can arise due to mutations (changes in DNA) of sperm cells from father and/or eggs from mother. De novo mutations are genetic alterations that are present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.
Current knowledge about how changes in the sperm and eggs of parents can be inherited by children, is based on genetic sequence analysis of blood from nuclear families. This involved comparison of the changes in DNA of children with that of their parents. Changes that are not present in the blood of parents are likely to have occurred in the sperm and egg of the father and mother.
Whilst studying the nuclear family is very useful in order to look at the level of diversity, it will only allow the investigators to study a small number of germ cells making it difficult to ascertain the overall level of diversity that is shown in the sperm and eggs of fathers and mothers. There is also little knowledge of how different factors such as ageing, smoking, BMI and exposure to carcinogens might affect the germ cells of adults and since changes in sperm and eggs can be transmitted to children, it is important to understand how disease causing mutations arise in reproductive tissues. Thus, how such changes can predispose children to rare disorders and cancer predisposition syndromes.
Previous studies have shown that the FGFR3 gene accumulates more mutations in normal testes during the natural ageing process which leads to the relative enrichment of mutated sperm over time. In rare cases, it can lead to testicular cancer (spermatocytic seminomas) in older men, but also it increases the likelihood of having children with Achondroplasia, which is caused by mutations in the FGFR3 gene in the sperm of the father.
Hence, the investigators aim is to determine the effect of different factors on the recurrence risk of pathogenic (disease causing) mutations in eggs and sperm.
- Conditions
- Predisposition, Genetic, Cancer, Mutation, Fertility Disorders
- Being tested
- sample collection
- Medical subject headings
- Genetic Predisposition to Disease, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
sample collectionOther
Collection of blood, skin, semen, urine and/or saliva samples. Access to previously collected tissue samples (if applicable).
| Study group | Role | What they receive |
|---|---|---|
| Individuals and Families affected by disease predisposition syndromes | We will work with collaborators to identify cohorts of families in which one or more members suffer with a cancer predisposition syndromes such as LFS. The affected individual/s act as an index participant and their unaffected family members act as controls. This may include immediate family (father, mother and affected/non-affected siblings) and extended family members (grandparents, maternal/paternal uncles and aunts) where practical.
We wish to collect blood samples, buccal swabs, skin swabs, saliva and/ or urine samples. Adult males (affected and unaffected) may (cohort dependant) also be asked to collect a semen sample for use in the study.
We will ask affected individuals if we can access any leftover tumour biopsies and/or material from medical procedures for use in the study.Material will only be accessed once it is not required for diagnostic purposes. Receives: Other: sample collection | |
| Individuals attending fertility clinics with or without fertility problems | For males who are attending fertility clinics we will require blood or saliva samples along with a semen sample as a minimum to take part in this arm of the study. Receives: Other: sample collection | |
| Individuals receiving treatment for cancers in the reproductive system | These participants will have to agree to donate a blood sample (and a semen sample for adult male participants) both before and after their treatment. If any participants do not wish to give a blood sample, we may be able to collect a saliva sample or buccal swab instead. Receives: Other: sample collection |
What is being measured
The primary outcome is the main question the study is designed to answer.
How often mutations accumulate in healthy reproductive tissues
Establish how often mutations (changes in DNA) accumulate in healthy reproductive tissues (testes and ovaries).
Measured: 7 years
Secondary outcomes (3)
Identification and Characterisation of Mutations
Determine the genetic changes in gonadal tissues, including the frequency, type, and nature of mutations acquired during germ cell production, and identify the genes and cellular processes that these mutations may alter.
Measured: 7 years
Comparative Analysis of Mutation Rates
Compare mutation rates in gonadal tissues across different age groups, sexes, and individuals with or without cancer predisposition syndromes.
Measured: 7 years
Inheritance and Transmission Risk
Assess the inheritance risk and rate of transmission of pathogenic mutations by analysing the proportion of germ cells carrying these mutations in affected individuals and comparing them to unaffected donors.
Measured: 7 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Sep 2024
- Study start20 Jun 2021
- Primary completion1 Mar 2027 (estimated)
- Study completion1 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Predisposition, GeneticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Other
- Enrolment
- 1,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Wellcome Sanger Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Raheleh Rahbari, Principal investigator, Wellcome Sanger Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06584994
- Sponsor's protocol ID
- 273194
- Status last verified
- Jul 2024
- First submitted
- 4 Jul 2024
- Last updated
- 5 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigating Clonal Dynamics in Gonads and Their Role in Disease Predisposition
- ClinicalTrials.gov ID
- NCT06584994
- Acronym / sponsor ID
- 273194
- Conditions
- Predisposition, Genetic, Cancer, Mutation, Fertility Disorders
- Study type
- Observational
- Recruitment status
- Enrolling by invitation
- Enrolment
- 1,000 participants (estimated)
- Lead sponsor
- The Wellcome Sanger InstituteUniversity, hospital or other
- Study start
- 20 Jun 2021 (actual)
- Primary completion
- 1 Mar 2027 (estimated)
- Study completion
- 1 Mar 2027 (estimated)
- First posted
- 5 Sep 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Gametogenesis is the production of sperm and eggs; it takes place through the process of meiosis. Gametogenesis is subject to the acquisition of mutations as with other processes in the body. Many of these mutations are somatic, meaning that they occur during life as part of the process of cell division rather than being passed down from parents. When somatic mutations take place during gametogenesis, there is the potential for hereditary genetic consequences. However, the processes that cause the mutations during gametogenesis and the implications they have for heritability and disease predisposition are poorly understood.
The goal of this research is to provide a detailed description of the genetic changes in gonadal tissues, and to understand how mutations acquired during the production of germ cells (sperm and eggs) contribute to the predisposition to a wide range of rare diseases and cancer predisposition in future offspring.
Detailed description
Predisposition to rare disorders and cancers can arise due to mutations (changes in DNA) of sperm cells from father and/or eggs from mother. De novo mutations are genetic alterations that are present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.
Current knowledge about how changes in the sperm and eggs of parents can be inherited by children, is based on genetic sequence analysis of blood from nuclear families. This involved comparison of the changes in DNA of children with that of their parents. Changes that are not present in the blood of parents are likely to have occurred in the sperm and egg of the father and mother.
Whilst studying the nuclear family is very useful in order to look at the level of diversity, it will only allow the investigators to study a small number of germ cells making it difficult to ascertain the overall level of diversity that is shown in the sperm and eggs of fathers and mothers. There is also little knowledge of how different factors such as ageing, smoking, BMI and exposure to carcinogens might affect the germ cells of adults and since changes in sperm and eggs can be transmitted to children, it is important to understand how disease causing mutations arise in reproductive tissues. Thus, how such changes can predispose children to rare disorders and cancer predisposition syndromes.
Previous studies have shown that the FGFR3 gene accumulates more mutations in normal testes during the natural ageing process which leads to the relative enrichment of mutated sperm over time. In rare cases, it can lead to testicular cancer (spermatocytic seminomas) in older men, but also it increases the likelihood of having children with Achondroplasia, which is caused by mutations in the FGFR3 gene in the sperm of the father.
Hence, the investigators aim is to determine the effect of different factors on the recurrence risk of pathogenic (disease causing) mutations in eggs and sperm.
Study design
- Observational model
- Other
- Time perspective
- Other
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Individuals and Families affected by disease predisposition syndromes | – | Other: sample collectionWe will work with collaborators to identify cohorts of families in which one or more members suffer with a cancer predisposition syndromes such as LFS. The affected individual/s act as an index participant and their unaffected family members act as controls. This may include immediate family (father, mother and affected/non-affected siblings) and extended family members (grandparents, maternal/paternal uncles and aunts) where practical. We wish to collect blood samples, buccal swabs, skin swabs, saliva and/ or urine samples. Adult males (affected and unaffected) may (cohort dependant) also be asked to collect a semen sample for use in the study. We will ask affected individuals if we can access any leftover tumour biopsies and/or material from medical procedures for use in the study.Material will only be accessed once it is not required for diagnostic purposes. |
| Individuals attending fertility clinics with or without fertility problems | – | Other: sample collectionFor males who are attending fertility clinics we will require blood or saliva samples along with a semen sample as a minimum to take part in this arm of the study. |
| Individuals receiving treatment for cancers in the reproductive system | – | Other: sample collectionThese participants will have to agree to donate a blood sample (and a semen sample for adult male participants) both before and after their treatment. If any participants do not wish to give a blood sample, we may be able to collect a saliva sample or buccal swab instead. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Children diagnosed with disease predisposition syndromes and/or cancer and their family members (mother, father, siblings) We may also include the wider family (maternal/paternal aunts, uncles and grandparents) Recruitment and the sequencing of both prospectively collected samples and those retrospectively collected from tissue banks will run for the first four years of the study.
Key inclusion criteria (4 listed)
- Minimum of child affected with cancer pre-disposition syndromes and their father
- Additional family members of consented father and child duos (Mother, same parent siblings, Maternal/Paternal Aunts, uncles and grandparents of affected child)
- Reproductive tissue samples from both men and women affected by cancer collected with consent for use in research.
- Reproductive tissue samples from both men and women unaffected by cancer collected with consent for use in research.
Key exclusion criteria (7 listed)
- Fathers who do not wish to donate a semen sample or are unable to will be excluded from the study, as will their families
- Fathers who have had a vasectomy will be excluded from the study as will their families
- Adults who do not have the capacity to consent for themselves will be excluded from the study.
- Families in which both parents do not have capacity to consent will also be excluded as they will be unable to give parental consent for their children's participation.
- In order to be eligible siblings must share the same two parents as the affected child, all other siblings will be excluded from the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| sample collectionCollection of blood, skin, semen, urine and/or saliva samples. Access to previously collected tissue samples (if applicable). | Other | Individuals and Families affected by disease predisposition syndromes, Individuals attending fertility clinics with or without fertility problems, Individuals receiving treatment for cancers in the reproductive system |
Primary outcome
How often mutations accumulate in healthy reproductive tissues
Time frame: 7 years
Establish how often mutations (changes in DNA) accumulate in healthy reproductive tissues (testes and ovaries).
3 secondary outcomes
Identification and Characterisation of Mutations
Time frame: 7 years
Comparative Analysis of Mutation Rates
Time frame: 7 years
Inheritance and Transmission Risk
Time frame: 7 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Sep 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Raheleh Rahbari principal investigator
Wellcome Sanger Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Predisposition, Genetic and Cancer, run by The Wellcome Sanger Institute at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: enrolling by invitation, as of the sponsor's last update on 5 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
How often mutations accumulate in healthy reproductive tissues (time frame: 7 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2024.