Main and long-term goal of this project is to gain more knowledge of the relationship between genome-wide genetic variation and the risk of breast cancer, in the context of a positive family history. This knowledge will improve individual risk…
ID
Source
Brief title
Condition
- Reproductive tract and breast disorders congenital
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. A rare high-risk mutation in a gene that is associated with breast cancer,
of relevance to the individual.
2. A common low-risk SNP-variation in a gene that is associated with breast
cancer, of relevance to the familial breast cancer group as a whole.
3. A genetic profile that occurs more often among affected family members than
among controls (sporadic patients or healthy subjects).
4. An association between the result of a functional assay on cell material of
study participants and disease status, at the individual or familial level.
5. A gene expression profile in cell material of study participants that is
associated with disease status, at the individual or familial level.
6. A proteomics profile in cell or serum material of study participants that is
associated with disease status, at the individual or familial level.
Secondary outcome
not applicable
Background summary
Genetic factors contribute signficantly to susceptibility to breast cancer, but
only a minority of them have been identified. Mutations and genetic variation
in about 20 genes are currently known to influence breast cancer risk; together
they explain almost 30% of the familial risk. The clinical geneticist can
counsel women with a positive family history for breast cancer. In 10-15% of
the families a pathogenic mutation in the BRCA1 or BRCA2 gene is detected. In
another 15% a variation is detected of which the clinical relevance is unclear.
This implies that in over 70% of the patients seeking counseling, risk
estimation is based solely on family anamnesis. Other known genes are presently
not incorporated in the risk assessment models, mainly because it is presently
unclear how the various genes interact with each other to determine individual
breast cancer risk.
Study objective
Main and long-term goal of this project is to gain more knowledge of the
relationship between genome-wide genetic variation and the risk of breast
cancer, in the context of a positive family history. This knowledge will
improve individual risk assessment for the development of breast cancer within
these families.
New, unknown genes could complement the genetic multifactorial model, while an
in-depth characterization of known genes in a large set of families will enable
the analysis of genetic interactions that may underlie familial clustering of
breast cancer. Ultimately, this will lead to a refinement of gene diagnostics
and an improvement of personal risk assessment for individuals from these
families.
Study design
We will collect DNA, serum, and fibroblasts of at least 100 probands from
eligible breast cancer families and 300-400 relatives. We will use the DNA for
the characterization of genetic variation associated with breast cancer. The
serum will be used for proteomic analyses if the technology will allow the
discovery of protein biomarkers from these samples. Fibroblast cultures can be
subjected to a variety of functional analyses, such as gene expression
profiling, or cellular response to genotoxic stress.
The detected genetic variation, gene expression and other biological parameters
will be analyzed within the framework of the family history of breast cancer.
This allows the detection of co-segregation of breast cancer and gene variant
in the family, but also, through a *genetical genomics* approach whether
various parameters co-segregate and thus have a genetic basis. This approach
could lead to the discovery of new genetic determinants for breast cancer, even
in the relatively small research population proposed here.
Study burden and risks
The following biomaterials will be collected from study participants:
1. DNA from blood lymphocytes
2. Blood serum
3. Skin biopsy (short term fibroblast cultures will be stored frozen)
The medical side-effects associated with sample collection are negligible.
Participants will be invited to visit the Department of Clinical Genetics. For
the proband, this means one extra visit (after 2 weeks respite for reflection);
for family members it will be a one-time visit. There will be no physical
examinations during these visits.
In addition, we will ask permission to request medical data regarding the tumor
diagnosis and the formalin-fixed paraffin-embedded tumor tissue. After sample
collection, there will be no contact with the proband and the family, except in
the case when research has led to insights into the personal breast cancer risk
that would be clinically relevant to the individual.
Albinusdreef 2
2333 ZA Leiden
NL
Albinusdreef 2
2333 ZA Leiden
NL
Listed location countries
Age
Inclusion criteria
- Patient has an elevated risk to develop breast cancer on the basis of her family history for the disease
- Patient has been tested for DNA mutations in BRCA1 and BRCA2
- If patient is known with breast cancer, she has at least two first- or second degree relatives with breast cancer
- If patient has no personal history of breast cancer, she has at least three first- or second-degree relatives with breast cancer
- Families are elible for inclusion if at least two breast cancer patients are alive at the time of ascertainment to donate blood and/or a skin biopsy
Exclusion criteria
1. Individuals younger than 18
2. Individuals with mental illnesses
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 | NL27093.058.09 |