Analyze processes related to DNA-damage in oocyte development and early-developmental stage embryos from BRCA1/2-mutation carriers compared to controls, using immunohistochemistry and RNA-Seq technology.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Breast neoplasms malignant and unspecified (incl nipple)
- Ovarian and fallopian tube disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
a) determine the presence of apoptosis, DNA damage, impaired spindle formation
or other cell division defects present in the studied biological samples
compared to controls. b) exploration and identification of the molecular
pathways associated with reduced ovarian reserve and oocyte/embryo competence
in BRCA1/2-mutation carriers.
Secondary outcome
NA
Background summary
It was recently reported that BRCA1-mutation carriers subjected to ovarian
stimulation for fertility preservation by oocyte or embryo cryopreservation,
produce a lower number of mature oocytes than non-carriers. If this is
confirmed in further studies it may imply that also women who undergo in vitro
fertilization (IVF) with preimplantation genetic diagnosis (PGD), to avoid
transmission of their BRCA mutation to offspring, produce less mature oocytes.
This would decrease the chance of a successful IVF/PGD procedure. In this
study, we focus on the molecular mechanisms that may lead to a reduced ovarian
reserve. We hypothesize that DNA-damage repair, in which BRCA1 and BRCA2 are
important players, is linked to oocyte maturation. There is some evidence for
this, since BRCA2-deficiency in animal models also results in impaired
oogenesis. Furthermore, irradiation (which causes DNA-damage) and mutations in
ATM (another DNA-damage repair gene) result in reduced ovarian reserve.
Study objective
Analyze processes related to DNA-damage in oocyte development and
early-developmental stage embryos from BRCA1/2-mutation carriers compared to
controls, using immunohistochemistry and RNA-Seq technology.
Study design
Cumulus cells, oocytes and early-developmental stage embryos will be collected
from female BRCA1/2-mutation carriers undergoing IVF/PGD, and healthy female
controls. Only residual material is used i.e. abnormal or non-fertilized
oocytes and embryos with the BRCA1/2 mutation or another autosomal dominant
genetic condition (controls), or the embryos are not used for transfer to the
patient or cryopreservation, due to insufficient quality. Immunohistochemistry
(IHC) for several proteins will be performed on this material, including
BRCA1/2, proteins involved in spindle formation during cell division,
DNA-damage repair and apoptotic machinery. Additionally, RNA will be isolated
to study the overall gene expression compared to controls. The expression data
obtained will be correlated to the clinical data to find molecular markers
associated with reduced fertility of women with BRCA-mutations upon hormonal
stimulation.
Study burden and risks
Neither risks nor any kind of extra burden to the patients are associated with
participation. This study does not require additional visits, physical
examinations or other tests, blood samples or other biological material other
than those required for the IVF/PGD or IVF procedure that these women will
undergo. Participation does not affect the IVF-treatment of the patient in any
way nor will it benefit the patients in any way at this stage.
P. Debyelaan 25
Maastricht 6229 HX
NL
P. Debyelaan 25
Maastricht 6229 HX
NL
Listed location countries
Age
Inclusion criteria
- IVF/PGD treatment for a BRCA1/2 mutation, both female and male mutation carriers
- IVF/PGD treatment because of an autosomal dominant genetic disorder transmitted by the male
- IVF treatment, including ICSI, for male subfertility
Exclusion criteria
- Previous diagnosis of female subfertility in controls
- Known hereditary disease other than due to BRCA1/2-mutations in the female
- Known history of a malignancy in the female
- History of cancer treatment in the female
- Non-Dutch couples, not able to understand the patient information to give
informed consent properly
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 | NL43360.000.13 |