Register for Fishing for microdeletions: now researchers can identify sections of DNA that predispose an embryo to develop cancer syndromes in later life
Wednesday 11 March 2009
Researchers have used a common laboratory technique for the first time to detect
genetic changes in embryos that could predispose the resulting children to
develop certain cancer syndromes. Current preimplantation genetic diagnosis
techniques can detect mutations in very small bits of genes or DNA, but, until
now, it wasn’t easy to detect deletions involving whole genes or long sections
of DNA in embryos.
The study, published online today (Wednesday 11 March) in Europe’s leading
reproductive medicine journal Human Reproduction [1], uses a
technique called fluorescent in situ hybridization (FISH) to detect losses of
small parts of whole chromosomes (microdeletions) in a single cell from an
embryo. The work opens the way to test for microdeletions in patients with other
genetic conditions as well as the two cancer predisposition syndromes treated in
this study. [2]
Professor Joris Vermeesch, coordinator of the Genomics Core and head of
Constitutional Cytogenetics, and Evelyne Vanneste, a PhD student, both at the
Center for Human Genetics, University Hospital Leuven (Belgium), and their
colleagues used FISH to carry out PGD in embryos from three couples where the
women carried microdeletions for either neurofibromatosis type 1 (NF1) or Von
Hippel-Lindau disease (VHL). As a result, the woman with the VHL mutation gave
birth to healthy twins from embryos selected using FISH PGD.
Neurofibromatosis type 1 (also known as Von Recklinghausen disease) is a common
inherited condition with an incidence at birth of one in 3,000-3,500. NF1
patients develop tumours of the nervous system, pigmented patches of skin and
can have lower IQs. In 95% of people with NF1, a mutation is found in the NF1
gene, which is a tumour suppressor gene; but five per cent of NF1 patients have
microdeletions of the gene, and large microdeletions can result in more severe
symptoms.
Von Hippel-Lindau (VHL) disease is a rarer cancer syndrome, occurring in about
one in 36,000 births. Symptoms of the disease include benign tumours of the
central nervous system and benign and malignant tumours of organs such as the
kidneys, adrenal glands and pancreas. It is an inherited condition caused by a
mutation in the VHL tumour suppressor gene.
The strands of DNA that twist together to form the double helix structure are
made up of lots of small sections called nucleotides. The nucleotides are made
up of the four DNA bases – adenine, thymine, guanine and cytosine (or A,T,C,G).
Mutations that can be detected by the conventional PCR (polymerase chain
reaction) technique used in PGD are usually mutations of a single nucleotide or
base. A deletion or microdeletion normally involves the loss of larger numbers
of nucleotides.
Prof Vermeesch explained: “Current techniques using PCR to detect abnormalities
in embryos can detect one base, nucleotide or letter change in the DNA, but they
cannot be used when a person has a loss of the whole gene or a lot of letters –
a microdeletion. Patients with these cancer predisposition syndromes, and some
other conditions, usually carry only a single microdeletion. Now, for the first
time, we have used FISH to detect these microdeletions in the embryo and thus
can help carriers to create offspring without those anomalies.
“Importantly, microdeletions are not so rare in neurofibromatosis type 1. It is
also becoming clear that genomic disorders caused by microdeletions,
duplications and copy number variations are much more frequent than previously
thought. The techniques we have used in this study will help a wide range of
microdeletion carriers.”
For each of the three women, the researchers created probes that could be used
to identify NF1 or VHL deletions in the embryos. The embryos were obtained from
the women using normal assisted reproduction techniques. They took two cells
from each embryo and performed FISH to probe them for the microdeletions. Only
embryos that FISH had identified as being healthy, without any microdeletions,
were transferred to the women’s wombs.
Ms Vanneste explained that although they had to make FISH probes specific to
each woman, the NF1 microdeletions found tended to recur. “Therefore, most NF1
patients with a deletion carry the same deletion and our FISH PGD conditions can
be rapidly replicated and re-used in other deletion carriers. It seems likely
that the number of families that can benefit from FISH PGD will increase in
years to come and we are continuing to help more families using this approach.
However, for each condition a new probe has to be made. This is time-consuming,
but we are currently developing tools to identify all similar genetic imbalances
with a single technology.”
[1] Preimplantation genetic diagnosis using fluorescent in situ
hybridization for cancer predisposition syndromes caused by microdeletions.
Human Reproduction. doi:10.1093/humrep/dep034
[2] PGD can be carried out already to detect a genetic
susceptibility for some cancers, but only if the specific mutation is know (e.g.
to detect the BRCA1/2 mutations that can lead to breast cancer developing). The
majority of these cases involve a change in a single nucleotide, not a
microdeletion.
Notes:
A pdf of the full research paper is available at:
http://www.oxfordjournals.org/eshre/press-release/freepdf/dep034.pdf
Human Reproduction is a monthly journal of the European Society of Human
Reproduction and Embryology (ESHRE), and is published by Oxford Journals, a
division of Oxford University Press.
Please acknowledge Human Reproduction as a source in any articles.
ESHRE’s website is: www.eshre.com
Abstracts of other papers in ESHRE’s three journals – Human Reproduction,
Molecular Human Reproduction and Human Reproduction Update – can be accessed
post embargo from
http://www.oxfordjournals.org/eshre
Papers are available on request from Emma Mason.
Contact (media enquiries only):
Emma Mason
Tel: +44 (0)1376 563090 Mobile: +44 (0)7711 296 986
Email: wordmason@mac.com
