The main objective of this study is to identify rare, high-penetrance germline mutations predisposing to familial and/or early onset UBC.
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are the presence of rare, novel, high-penetrance
mutations predisposing for familial or early-onset bladder cancer, and
second-hit (somatic) mutations (found in tumor DNA).
Secondary outcome
The secondary study parameter is information on disease characteristics (tumor
stage, tumor grade).
Background summary
Urinary bladder cancer (UBC) is a common disease, which has a significant
impact on patients due to the high risk of multiple recurrences leading to
frequent transurethral procedures in non-muscle invasive disease and major
surgery in muscle invasive disease. A positive family history of UBC doubles
the risk for UBC and suggests a role for germline, genetic variants in the
etiology of UBC. Common genetic UBC variants were successfully tackled in
genome-wide association studies in large populations of sporadic UBC cases and
controls. However, we currently know little about rare genetic variants
involved in bladder cancer predisposition. Identification of these variants
leads to increased insight into the mechanisms of UBC biology, offering novel
potential targets for therapeutic interventions and new diagnostic and
prognostic markers. We will make use of a selection of UBC samples that are
enriched for these rare, novel, high-penetrance variants: striking families and
early-onset cases.
Study objective
The main objective of this study is to identify rare, high-penetrance germline
mutations predisposing to familial and/or early onset UBC.
Study design
We will perform an observational family study using high-risk families and
patient-parent trios. The duration of the study is four years. This study will
be divided in three parts:
1. A nationwide recruitment of novel index patients and families including
extremely early age-at-onset patients and their healthy parents. We will make
use of our collection of UBC families (N=64). We will i) invite previously
identified high-risk UBC families to a consultation with a clinical geneticist
in order to update the information on family history of cancer and exposure to
UBC risk factors in the family ii) extend the collection of peripheral blood
from affected and unaffected UBC family members and iii) collect tumor material
from UBC index patients and affected family members. If a new high-risk UBC
family is identified, the clinical geneticist will draw a pedigree with
information on family history of cancer, collect information on exposure to UBC
risk factors in the family, and collect DNA of the index patient and selected
family members.
We will also recruit extremely young UBC patients (<=30 years of age at time of
UBC diagnosis) with help of the Netherlands Cancer Registry and of the treating
physicians of the patients. From the early-onset patients and their healthy
parents we will collect two EDTA blood tubes. From the early-onset patients we
will also collect remaining tumor tissue.
2. Discovery of novel candidate UBC-predisposing mutations and genes. We will
employ next generation whole exome sequencing (WES) on the germline DNA of two
relatives with UBC from 20 stringently selected high-risk families, and 25
extremely young sporadic UBC patients and their unaffected parents (trios) to
identify germline de novo mutations as well as variants that follow a recessive
inheritance pattern. This will result in ~100 candidate genes for the third
part of this study.
3. Substantiation of novel candidate UBC-predisposing genes in additional
samples. Based on the selection of candidate genes obtained using WES, we will
assemble a set of an anticipated 100 candidates to perform a high-throughput
mutational screening using molecular inversion probe (MIP) technology. Our
screening series comprises the germline DNAs of the entire set of index
patients and relatives of UBC families (N=±145), the extremely early-onset
bladder cancer patients (N=±150), and their unaffected parents. In addition, we
will include tumor DNA from familial patients and early-onset patients for the
detection of second-hit mutations and somatic changes in these selected
candidate genes.
Study burden and risks
Burden and risk associated with participation
High-risk UBC families: The index patients of 64 high-risk UBC families
(identified for a previous study) are contacted by the clinical geneticist
involved in this project for a consultation, during which information on family
history and exposure to UBC risk factors in the family is updated. Affected
family members (and selected non-affecteds) for whom no DNA has been collected
yet, are asked to donate a blood (two 9mL EDTA tubes) or saliva sample. For new
high-risk UBC families, the index patient will be invited to have a
consultation with the clinical geneticist, during which a pedigree is drawn
with information on family history of cancer and information on exposure to UBC
risk factors in the family is collected. The index patient and selected family
members are asked to donate a blood sample. The blood drawing will be performed
at the outpatient clinic of the Genetics department at the Radboudumc, or one
of the local Thrombosis Service Points in the country if deemed more
convenient. Risks associated with giving a single blood sample are confined to
fainting or bruising and are therefore negligible.
On the informed consent form participants give permission for genetic research
with the chance of incidental findings (unless they state on the informed
consent form that only research without the chance of incidental findings may
be performed). Any incidental findings are discussed by an independent
commission that decides whether returning the incidental finding is beneficial
to the participant. If so, the participant is invited for a consultation with
the clinical geneticist involved in this project.
Early-onset patients and their parents: The patients will be asked to fill out
a detailed bladder cancer specific questionnaire about family history, medical
history, socio-demographic data (age, gender, ethnicity, education, occupation)
and lifestyle factors (e.g. smoking behaviour). The patients are asked to fill
out the contact information of their parents on the questionnaire. The patients
as well as their parents are asked to donate a blood (two 9mL EDTA tubes) or
saliva sample. The blood drawing will be performed by a professional at one of
the Thrombosis Service Points. Again, risks associated with giving a single
blood sample are confined to fainting or bruising and are therefore negligible.
Also, the early-onset patients and their parents give permission for genetic
research with the chance of incidental findings (unless they state on the
informed consent form that only research without the chance of incidental
findings may be performed).
Benefit associated with participation
Participants can possibly benefit from this study if a mutation that underlies
the bladder cancer (in their family) is identified. Family members (and any
future children) can be genotyped for this mutation and periodically screened
if needed. Furthermore, participants may consider the possible sequencing of
their genetic material and the potential returns of incidental findings, a
benefit.
Group relatedness
The research is (partially) focused on patients who are not yet 18 because the
probability of an underlying mutation as genetic cause for the bladder tumor is
greatest in the group of patients with a young age at onset. It is also in the
interest of the young patients and their families (and any future children) to
include them in the study at a young age and allow for the identification of
any causal mutation as soon as possible.
Geert Grooteplein Noord 21
Nijmegen 6525 EZ
NL
Geert Grooteplein Noord 21
Nijmegen 6525 EZ
NL
Listed location countries
Age
Inclusion criteria
Newly identified high-risk UBC families:
- Hereditary UBC: A family with at least three first-degree relatives with UBC, or a family with two first-degree relatives with UBC with uncommon characteristics (such as young never-smoking women with high-stage disease).;Early-onset patients:
- Diagnosed with bladder cancer after 01-01-1989
- <= 30 years old at time of diagnosis
Exclusion criteria
High-risk UBC families:
- Unable to read or understand the invitation letter, information brochure and informed consent form;Early-onset patients:
- Unable to read or understand the invitation letter, information brochure and informed consent form
- Younger than 12 years at time of study invitation
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
CCMO | NL51321.091.14 |