The majority of hereditary cancer syndromes are inherited in an autosomal dominant fashion. Thus, offspring have a 50% chance of inheriting the condition, as well as a 50% chance of not inheriting it. Odds change when both parents are carriers of a syndrome and in cases of X-linked or recessive conditions. For example, when both parents are carriers of a BRCA2 mutation, offspring also are at risk of developing an autosomal recessive disorder called Fanconi anemia. In the case of BRCA1, it is believed that inheriting a mutation from both parents is lethal, and the pregnancy would not be viable. Thus, the chance of a child having a BRCA1 mutation would be 75%, and the chance of not being a carrier would be 25%.
It is well known that individuals with a hereditary cancer syndrome sometimes worry about passing the gene mutation on to their children.1-3 This is true regardless of whether the carrier is a man or a woman. Both genders also have expressed interest in learning about reproductive options that prevent transmission of the mutated gene. However, studies demonstrate that the majority of individuals are not aware of reproductive options, such as preimplantation genetic diagnosis (PGD). For this reason, it is important that healthcare providers offering cancer genetic testing make themselves aware of such options. In fact, the NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian4 include a section on reproductive options in the management sections for BRCA1/2, Cowden syndrome, and Li-Fraumeni syndrome. Such options include both post- and preconception genetic diagnosis.
For post- or preconception genetic diagnosis to occur, the causative gene mutation for the syndrome must be known. Postconception options involve testing during pregnancy to determine whether the fetus carries the mutation of interest. This is done by chorionic villus sampling (CVS) or amniocentesis. With CVS, placental cells are biopsied, whereas with amniocentesis, fluid around the fetus is sampled. Typically, CVS is performed between 10 and 12 weeks, and amniocentesis is done between 15 and 18 weeks. Both slightly increase the risk of miscarriage and have their own limitations. With both procedures, the condition of interest is diagnosed during pregnancy, and thus parents are faced with a decision about whether to terminate the pregnancy. Many individuals do not want to be faced with this decision, and PGD provides another option.
What Is PGD?
PGD provides an alternative to postconception diagnostic options. It involves in vitro fertilization (IVF) followed by removal of 1 or 2 cells at the 6- to 8-cell stage. The biopsied cells are then analyzed for the condition of interest, which allows for the selection and transfer of only unaffected or affected embryos to the uterus. For example, in the case of a TP53 mutation (Li-Fraumeni syndrome), it would be determined which embryos have the TP53 mutation and which do not. The parents then select to transfer either those with or without the TP53 mutation. CVS or amniocentesis is sometimes recommended to confirm the diagnosis.
The first birth of a baby utilizing PGD occurred in 1990. Early uses of PGD were for aneuploidy screening and for couples at risk for X-linked recessive diseases and involved sexing, as females would not be affected. Use then expanded to include other single-gene, highly penetrant conditions, such as cystic fibrosis, Tay-Sachs, and Huntington’s disease. The first use of PGD for an inherited cancer syndrome occurred in 1997 for familial adenomatous polyposis (FAP).5 Cancer syndromes, such as FAP, vary widely with regard to penetrance, age of onset, type of cancer, and prevention or treatment options. These variables make them unique from highly penetrant conditions for which PGD was initially used, and some experts find its use more controversial. However, when developing guidelines and policy, it is also important to seek the opinion of the affected group.
Several studies have examined the knowledge and beliefs of PGD in the hereditary cancer community. The majority of studies have focused on the BRCA1/2 community and have found that most individuals with a BRCA mutation feel PGD should be an option regardless of whether they would personally use it.1,2,6,7 Additionally, more individuals would consider PGD over prenatal diagnosis.6 Similar views are shared by individuals with Peutz-Jeghers syndrome, Lynch syndrome, FAP, and multiple endocrine neoplasia (MEN).8,9 Furthermore, the majority of individuals were unaware of the option of PGD prior to the study.2,3,7,9
Data on how individuals would like to receive information about PGD are scarce. However, available results suggest carriers would like to be briefly informed about the subject and to receive a pamphlet with additional information. Also, they want the option of having a more detailed discussion at a later date. They may prefer to have that discussion with a clinician they already have a relationship with, such as their primary care provider, obstetrician, and/or oncologist.1 Although the focus of prenatal or preconception genetic diagnosis information dissemination is on individuals of reproductive age, it is important to take into consideration that many individuals are not diagnosed with cancer until after childbearing. However, these individuals may inform their at-risk family members about such options. As oncology nurses often have long-term relationships with patients and their families, even if they are not performing genetic testing, they should be aware of the option of PGD.
- The majority of individuals with a hereditary cancer syndrome feel PGD should be an option regardless of whether they would use it themselves
- Individuals who have completed childbearing may still be interested in reproductive options for family members, such as children and/or siblings
- Awareness of PGD is low, highlighting the importance of both patient and provider education
1. Hurley K, Rubin LR, Werner-Lin A, et al. Incorporating information regarding preimplantation genetic diagnosis into discussions concerning testing and risk management for BRCA1/2 mutations: a qualitative study of patient preferences. Cancer. 2012;118(24):6270-6277.
2. Ormondroyd E, Donnelly L, Moynihan C, et al. Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis. Eur J Hum Genet. 2012;20(1):4-10.
3. Quinn GP, Vadaparampil ST, Miree CA, et al. High risk men’s perceptions of pre-implantation genetic diagnosis for hereditary breast and ovarian cancer. Hum Reprod. 2010;25(10): 2543-2550.
4. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 4.2013. http://www.nccn.org/
professionals/physician_gls/f_guidelines.asp#genetics_screening. Accessed December 23, 2013.
5. Ao A, Wells D, Handyside AH, et al. Preimplantation genetic diagnosis of inherited cancer: familial adenomatous polyposis coli. J Assist Reprod Genet. 1998;15(3):140-144.
6. Menon U, Harper J, Sharma A, et al. Views of BRCA gene mutation carriers on preimplantation genetic diagnosis as a reproductive option for hereditary breast and ovarian cancer. Hum Reprod. 2007;22(6):
7. Vadaparampil ST, Quinn GP, Knapp C, et al. Factors associated with preimplantation genetic diagnosis acceptance among women concerned about hereditary breast and ovarian cancer. Genet Med. 2009;11(10):757-765.
8. van Lier MG, Korsse SE, Mathus-Vliegen EM, et al. Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis. Eur J Hum Genet. 2012;20(2):236-239.
9. Rich TA, Miu M, Etzel CJ, et al. Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer. 2013. Epublished ahead of print.