Investigate the association between BRCA1/2-mutations, DNA damage, apoptosis and oocyte/embryo quality in immature germinal vesicle (GV) bearing oocytes, immature metaphase 1 (MI) and unfertilized mature metaphase 2 (MII) oocytes and affected early-…
ID
Source
Brief title
Condition
- Reproductive tract and breast disorders congenital
- Breast neoplasms malignant and unspecified (incl nipple)
- Breast disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Morphology, the presence of apoptosis, DNA damage and chromosomal aberrations
in the (im)mature oocytes and embryos of BRCA1/2-mutation carriers compared to
oocytes and embryos of controls.
Secondary outcome
NA
Background summary
Previously, it has been shown that females carrying a BRCA1-mutation produce
less mature oocytes upon ovarian stimulation compared to non-carriers. Mice
carrying a Brca1-mutation also have less primordial follicles and their oocytes
and surrounding ovarian tissue show more DNA damage. In addition, Brca1-mutant
embryos also have increased amounts of numerical and structural chromosomal
aberrations after γ-irradiation compared to wild-type and heterozygous litter
mates. These suggest that female BRCA1-mutation carriers undergoing in vitro
fertilization (IVF) with or without pre-implantation genetic diagnosis (PGD),
to avoid transmission of their BRCA1-mutation to offspring, would have a
decreased chance on a successful IVF/PGD procedure. These results also suggest
that the quality of the embryos of female BRCA1-mutation carriers could be
diminished. At the moment, the mechanism behind these clinical observations is
not clear. We hypothesize that a decrease in ovarian reserve is the result of
an increase in DNA damage in oocytes, leading to an increased induction of
apoptosis and chromosomal instability. This is plausible since BRCA1, as well
as BRCA2, plays an important role in the repair of DNA damage.
Study objective
Investigate the association between BRCA1/2-mutations, DNA damage, apoptosis
and oocyte/embryo quality in immature germinal vesicle (GV) bearing oocytes,
immature metaphase 1 (MI) and unfertilized mature metaphase 2 (MII) oocytes and
affected early-developmental stage embryos from BRCA1/2-mutation carriers
compared to controls.
Study design
Prospective cohort study.
Human (im)mature oocytes and embryos of females undergoing IVF/PGD treatment
will be collected. Only residual material will be used, i.e. GV, MI oocytes,
unfertilized MII oocytes and embryos with the BRCA1/2-mutation or with another
genetic disorder, diagnosed by PGD. To determine oocyte and embryo quality,
their morphology will be scored during IVF procedure. By using
immunocytochemical staining of the acquired material, DNA damage and apoptosis
will be investigated. SNP arrays will be used to screen for structural and
numerical chromosomal variations genome-wide and determine parental origin.
Study burden and risks
Participation in the study will not involve any risk or additional burden for
the patient. No additional visits, physical examinations or other tests, blood
samples or other biological material other than those already required for
IVF/PGD is needed. Participation has no effect on IVF treatment of the patient
nor will it have an added value for the patient at this stage of the study.
P. Debyelaan 25
Maastricht 6229HX
NL
P. Debyelaan 25
Maastricht 6229HX
NL
Listed location countries
Age
Inclusion criteria
-IVF/PGD treatment for a BRCA1/2-mutation, both male and female mutation carriers (Control group A and Test group, respectively)
-IVF/PGD treatment because the male partner has an autosomal dominant hereditary disorder (such as but not restricted to Huntingtons disease or Marfan syndrome) or both male/female partners carry a autosomal recessive hereditary disorder (such as but not restricted to cystic fibrosis or spinal muscular atrophy )(Control group B)
Exclusion criteria
- Known hereditary disease other than due to BRCA1/2-mutations in the female
- Known genetic abnormalities in female leading to diminished ovarian reserve: carriers of fragile X syndrome or abnormalities of the X-chromosome
- Hereditary disease in male known to affect embryo development
- Known history of a malignancy in the female
- Endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or renal)
- History of cancer treatment in the female or male
- 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 | NL50432.000.14 |