Background: Hereditary Cancer and the role of PGD

Preimplantation genetic diagnosis – PGD, is a recently developed technology that allows testing of embryos during in vitro fertilization – IVF. Testing can be directed toward finding common problems such as embryos that have too many or too few chromosomes. These conditions cause miscarriages, birth defects and fetal or neonatal deaths. Other types of


testing can look for gene mutations that can cause cancer.

Family studies have revealed that some types of cancers are heredity. In some cases, scientists have identified a specific gene mutation, which is associated with the development of the cancer. Although, it generally takes more than one gene mutation to cause cancer, people with a single gene mutation may be at greater risk for developing the cancer.

For example, researchers believe that 1 in 10 cases of prostate cancer are inherited. In men who are diagnosed before age 55, however, almost half the cases are thought to be inherited.

Recently, scientists identified a gene mutation that appear to be linked to inherited prostate cancer. This mutation is found in only a small percentage of patients with inherited prostate cancer, however. It is very likely that there are other gene mutations, which are yet undiscovered, that may account for the other cases of inherited prostate cancer.

Probably one of the best-known examples of a cancer that is linked to a gene mutation is breast cancer. Inherited mutations account for about one fourth of all cases of breast cancer. For several years, a blood test has been available that screens for two gene mutations called BRCA1 and BRCA2. These gene mutations account for 4% of all cases of breast cancer.

For families that are plagued by hereditary cancer, there previously were no methods available that enabled them to avoid passing cancer on to future generations.

By using PGD, prospective parents can elect to attempt pregnancy with embryos that do not have the cancer causing mutations. Their children can then avoid the cancers that have stricken those families for generations. It is likely, that these children would not be at any greater risk for these cancers than anyone in the general population.

Cancers for which PGD has been performed

Syndrome Gene
Breast / Ovarian cancer BRCA1, BRCA2
Familial adenomatous polyposis APC
Gorlin syndrome PTCH
Hereditary nonpolyposis colorectal cancer MLH1, MSH2, MSH6, PMS2
LH-Fraumeni syndrome TP53
Multiple endocrine neoplasia Type 2a RET
Neurofibromatosis 1 NF1
Neurofibromatosis 2 NF2 / merlin
Rhabdoid predisposition syndrome hsnF5
Retinoblastoma RB1
Tuberous sclerosis complex TSC1, TSC2
Von Hippel-Lindau disease VHL

Source: JAMA, December 13, 2006—Vol 296, No. 22

How is a gene mutation in an embryo found?

First, the couple wishing to conceive must have blood testing. The parent whose family has hereditary cancer will be tested to see if he or she carries the cancer causing gene mutation. Usuaully, blood from an already affected family member will be required. Both partners will have several DNA markers mapped and identified. These markers will be used to help identify what segments of DNA are present in the embryos.

If a gene mutation is present in the DNA of one of the members of the couple, a molecular probe is created that will be able to find and attach to the area of the chromosome where the gene mutation is located. If the gene itself has not been identified but the area where the gene is located is known, then markers on the chromosome close to the mutation can be used to identify affected embryos.

Using enzymes to cut DNA in certain, specific spots is performed. DNA pieces of different sizes can be produced and then separated. DNA which contains a gene mutation will result in pieces of different size to form and these can then be tetected by analysis of the size of the DNA fragments.

How is IVF and PGD performed?

PGD is performed during an IVF cycle. Pre-testing is performed on all couples that are going to undergo IVF. For the female, this includes assessment of her ovarian reserve and uterine cavity. For the male, a semen analysis is performed. Problems that may affect the likelihood for IVF to succeed are addressed bofore stating treatment.

Once the plan for identifying affected embryos is set, then the couple will initiate then in-vitro fertilization cycle. The female will take injectable fertility medications to stimulate the development and maturation of multiple eggs. She will be monitored during this time with blood tests and ultrasounds to follow the growth and development of the eggs in her ovaries.

At the point at which egg maturity is reached, the woman undergoes an egg retrieval to remove the eggs. The male will collect a semen specimen at that time.

In the laboratory, the eggs are observed under a microscope. Each egg that has matured and is healthy appearing will be injected with one sperm from the male. this process is known as ICSI or intracytoplasmic sperm injection. The injected egg will be placed into an incubator overnight. The next morning, the injected eggs are inspected to determine which ones have fertilized. The fertilized egg will then undergo a polar body biopsy. The polar body is a cell which is extruded by the egg but which contains genetic material that can be tested. The embryos will be placed back into the incubator for two more days. On the third day the embryos are removed and the viable embryos are biopsied again. This is known as the blastomere biopsy The embryos are placed back into the incubator for a final two days.

On the 5th day after the eggs were removed from the ovaries, the embryo development is assessed. Viable embryos will then be matched with the PGD results. If there are viable embryos that are not carriers for the cancer causing gene mutation, then these embryos may be used for embryo transfer. In some cases, it may be possible to perform other types of testing on the embryos such as routine testing for abnormalities in the number of chromosomes. This may not be possible in all cases, however.

The number of embryos transferred to the uterus will depend in large part on the age of the female, the desire to avoid multiple pregnancy, and the number of embryos available after PGD testing.Typically, for women under 38 years of age, two embryos will be transferred.

One week after the embryo transfer, the female will return to our office for a pregnancy test. If pregnancy has been achieved, then we will monitor the early portion of the pregnancy before we send her back to obstetrician for routine obstetric care.