Preimplantation Diagnosis for Genetic Susceptibility
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《新英格兰医药杂志》
On May 10, 2006, the regulator of assisted reproduction in the United Kingdom — the Human Fertilisation and Embryology Authority (HFEA) — decided to include susceptibilities to certain cancers in the conditions for which it will allow preimplantation genetic diagnosis (PGD).1 In Britain, as in most of Europe, PGD refers to the removal of a single cell from an embryo generated in vitro for genetic testing to diagnose a recurrent, serious, heritable condition and thereby to avoid the implantation of affected embryos (see diagram). The technique is used by fertile couples, as an alternative to prenatal diagnosis with the use of amniocentesis or chorionic-villus sampling, to avert the abortion of an affected fetus. (In the United States, PGD also includes what most Europeans call "preimplantation screening": screening of the embryos of infertile couples for sporadic chromosomal aneuploidies, in order to improve the likelihood of implantation and reduce the risk of miscarriage.) Why is the decision of the HFEA newsworthy when PGD has been performed for predispositions to cancer in the United States and other countries since 2001?2
In Vitro Fertilization and Preimplantation Genetic Haplotyping.
Embryos are created with the use of in vitro fertilization. On the third day after fertilization, a single cell is removed from each embryo for genetic testing. After whole-genome amplification, the DNA is tested for the presence of a large series of specific short-tandem-repeat loci closely linked to the mutation causing the susceptibility. This testing will reveal contamination by extraneous DNA and provide sufficient information for a diagnosis to be made with the use of genetic-linkage analysis, even without precise knowledge of the mutation sequence. Up to two mutation-free embryos are considered for transfer back to the uterus.
Unlike the United States, where there is no government regulation of PGD (nor indeed of in vitro fertilization), Britain strictly regulates PGD practices, perhaps reflecting a historical public wariness of advances in assisted reproductive technology. In 1985, a senior member of Parliament, Enoch Powell, reflecting the views of a minority of the British public, introduced a bill to protect human embryos by disallowing research involving them and requiring all eggs fertilized in vitro to be transferred to the woman's uterus. The bill was only narrowly defeated in Parliament; had it passed, it would have severely limited the effectiveness of and advances in assisted reproductive treatment, in a manner similar to that of the prohibitive legislation now in effect in Germany and Austria and recently enacted in Italy.
Sensitive to the vociferous minority in the United Kingdom that opposed assisted reproduction because it viewed embryos as human beings, in 1990 the government passed the Human Fertilisation and Embryology Act, giving some protection to embryos — limiting the time they could be kept in vitro to 14 days and requiring licenses to be obtained for assisted reproductive therapy and for the storage of embryos and research involving them. This act also established the HFEA, which was empowered to regulate and enforce the strict limits laid out in a code of practice. The act permits (but only under license) treatments involving the biopsy and testing of embryos and allows embryos to be excluded from implantation in order to avoid the transmission of serious genetic diseases, but it does not define "serious." To perform PGD, clinics had to apply to the HFEA for a license to test for each new disease they wanted to include, and the authority decided whether the disease was sufficiently serious to warrant interference with the embryo and whether the clinic was competent to carry out the testing. The testing for some specific, highly penetrant single-gene defects, including late-onset diseases such as Huntington's disease, has been permitted, as has testing for chromosomal rearrangements.
But testing for susceptibilities is different. First, the likelihood that a child will acquire a disease such as breast cancer, ovarian cancer, hereditary nonpolyposis colorectal cancer, or familial adenomatous polyposis in adulthood varies according to the penetrance of the condition. And second, these sorts of conditions are amenable to preventive treatment — mastectomy and oophorectomy in the case of BRCA1 or BRCA2 mutations, for instance, and colectomy in cases of a mutation in HNPCC (which causes hereditary nonpolyposis colon cancer) or APC (which causes familial adenomatous polyposis).
Recognizing that the public would have an opinion on such a fundamental change in policy, the HFEA undertook a public consultation exercise, called "Choices and Boundaries,"3 which explored the ethical and practical issues raised by susceptibility testing. Then the decision was made in principle to allow testing for such conditions. "We have looked very carefully at the issues around the use of PGD embryo testing for families who carry susceptibility genes for cancers such as breast cancer and similar conditions," said Dame Suzi Leather, chair of the HFEA. "This included a detailed process of gathering public views, discussions with genetic interest groups, cancer charities, geneticists, and leading clinicians, alongside work by the policy team of the HFEA. The decision deals only with serious genetic conditions that we have a single-gene test for. We would not consider mild conditions — like asthma and eczema — which can be well managed in medical practice. We would not consider conditions like schizophrenia, where a number of genes have been identified but there is no single gene that dictates the condition."
This decision was welcomed by clinicians, professional societies, and patient groups, because it recognizes that any opportunity to reduce the likelihood of cancer contributes to good preventive medicine and that the seriousness of any condition will be perceived differently by families that have different experiences with its effects. The range of diseases for which PGD may be performed increases weekly in response to requests from patients, and with the advent of preimplantation haplotyping,4 many more diseases and susceptibilities can be tested for, provided that genealogic information is available.
The tight regulatory controls and cumbersome licensing requirements for interfering with a three-day-old, eight-cell embryo in vitro contrast sharply with the absence of regulatory controls for prenatal diagnosis. The only statutory requirement related to prenatal diagnosis in the United Kingdom is that physicians report the occurrence of any subsequent pregnancy termination and the reasons for it. Such termination may be performed at any time during gestation if "there is a substantial risk that if the child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped." The reasons for termination are not immune to challenge — recently, an abortion performed at more than 24 weeks of gestation because of a cleft lip and palate was legally challenged by a trainee vicar who discovered it as she studied abortion statistics, though the physicians were ultimately not charged with a crime5 — but the absence of a time limit on some terminations of pregnancy is at odds with the strict limits for protecting the embryo in vitro.
It was a quirk in parliamentary procedure that allowed the "prolife" lobby to revisit the provisions of the 1967 Abortion Act during the debate on fertilization and embryology. The lobby succeeded in reducing the overall time limit for abortion from 28 weeks to 24 weeks, but not in cases in which the child could have serious mental or physical handicaps. These clauses now stand within the Human Fertilisation and Embryology Act.
The HFEA and the 1990 act that created it have served the British well and have provided a good model for regulation of assisted conception. But the act needs attention in this rapidly changing field, and the British government has indicated that it is under revision. It is also time for the government to remove the clauses of the Abortion Act that sit so uncomfortably within the Human Fertilisation and Embryology Act and to deal with the inconsistencies highlighted by the recent deliberations about PGD and susceptibility to disease.
Source Information
Prof. Braude is the head of the Department of Women's Health at King's College London, School of Medicine, London.
References
Human Fertilisation and Embryology Authority. (Accessed July 20, 2006, at http://www.hfea.gov.uk/cps/rde/xchg/SID-3F57D79B-DA4AC4C5/hfea/hs.xsl/1124.html.)
Rechitsky S, Verlinsky O, Chistokhina A, et al. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online 2002;5:148-155.
HFEA consultations. (Accessed July 20, 2006, at http://www.hfea.gov.uk/cps/rde/xchg/SID-3F57D79B-DA4AC4C5/hfea/hs.xsl/380.html.)
Renwick PJ, Trussler J, Ostad-Saffari E, et al. Proof of principle and first cases using preimplantation genetic haplotyping -- a paradigm shift for embryo diagnosis. Reprod Biomed Online 2006;13:110-119.
Meikle J. Cleft lip abortion done `in good faith.' Guardian. March 17, 2005. (Accessed July 12, 2006, at http://www.guardian.co.uk/uk_news/story/0,3604,1439312,00.html.)(Peter Braude, M.B., B.Ch.)
In Vitro Fertilization and Preimplantation Genetic Haplotyping.
Embryos are created with the use of in vitro fertilization. On the third day after fertilization, a single cell is removed from each embryo for genetic testing. After whole-genome amplification, the DNA is tested for the presence of a large series of specific short-tandem-repeat loci closely linked to the mutation causing the susceptibility. This testing will reveal contamination by extraneous DNA and provide sufficient information for a diagnosis to be made with the use of genetic-linkage analysis, even without precise knowledge of the mutation sequence. Up to two mutation-free embryos are considered for transfer back to the uterus.
Unlike the United States, where there is no government regulation of PGD (nor indeed of in vitro fertilization), Britain strictly regulates PGD practices, perhaps reflecting a historical public wariness of advances in assisted reproductive technology. In 1985, a senior member of Parliament, Enoch Powell, reflecting the views of a minority of the British public, introduced a bill to protect human embryos by disallowing research involving them and requiring all eggs fertilized in vitro to be transferred to the woman's uterus. The bill was only narrowly defeated in Parliament; had it passed, it would have severely limited the effectiveness of and advances in assisted reproductive treatment, in a manner similar to that of the prohibitive legislation now in effect in Germany and Austria and recently enacted in Italy.
Sensitive to the vociferous minority in the United Kingdom that opposed assisted reproduction because it viewed embryos as human beings, in 1990 the government passed the Human Fertilisation and Embryology Act, giving some protection to embryos — limiting the time they could be kept in vitro to 14 days and requiring licenses to be obtained for assisted reproductive therapy and for the storage of embryos and research involving them. This act also established the HFEA, which was empowered to regulate and enforce the strict limits laid out in a code of practice. The act permits (but only under license) treatments involving the biopsy and testing of embryos and allows embryos to be excluded from implantation in order to avoid the transmission of serious genetic diseases, but it does not define "serious." To perform PGD, clinics had to apply to the HFEA for a license to test for each new disease they wanted to include, and the authority decided whether the disease was sufficiently serious to warrant interference with the embryo and whether the clinic was competent to carry out the testing. The testing for some specific, highly penetrant single-gene defects, including late-onset diseases such as Huntington's disease, has been permitted, as has testing for chromosomal rearrangements.
But testing for susceptibilities is different. First, the likelihood that a child will acquire a disease such as breast cancer, ovarian cancer, hereditary nonpolyposis colorectal cancer, or familial adenomatous polyposis in adulthood varies according to the penetrance of the condition. And second, these sorts of conditions are amenable to preventive treatment — mastectomy and oophorectomy in the case of BRCA1 or BRCA2 mutations, for instance, and colectomy in cases of a mutation in HNPCC (which causes hereditary nonpolyposis colon cancer) or APC (which causes familial adenomatous polyposis).
Recognizing that the public would have an opinion on such a fundamental change in policy, the HFEA undertook a public consultation exercise, called "Choices and Boundaries,"3 which explored the ethical and practical issues raised by susceptibility testing. Then the decision was made in principle to allow testing for such conditions. "We have looked very carefully at the issues around the use of PGD embryo testing for families who carry susceptibility genes for cancers such as breast cancer and similar conditions," said Dame Suzi Leather, chair of the HFEA. "This included a detailed process of gathering public views, discussions with genetic interest groups, cancer charities, geneticists, and leading clinicians, alongside work by the policy team of the HFEA. The decision deals only with serious genetic conditions that we have a single-gene test for. We would not consider mild conditions — like asthma and eczema — which can be well managed in medical practice. We would not consider conditions like schizophrenia, where a number of genes have been identified but there is no single gene that dictates the condition."
This decision was welcomed by clinicians, professional societies, and patient groups, because it recognizes that any opportunity to reduce the likelihood of cancer contributes to good preventive medicine and that the seriousness of any condition will be perceived differently by families that have different experiences with its effects. The range of diseases for which PGD may be performed increases weekly in response to requests from patients, and with the advent of preimplantation haplotyping,4 many more diseases and susceptibilities can be tested for, provided that genealogic information is available.
The tight regulatory controls and cumbersome licensing requirements for interfering with a three-day-old, eight-cell embryo in vitro contrast sharply with the absence of regulatory controls for prenatal diagnosis. The only statutory requirement related to prenatal diagnosis in the United Kingdom is that physicians report the occurrence of any subsequent pregnancy termination and the reasons for it. Such termination may be performed at any time during gestation if "there is a substantial risk that if the child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped." The reasons for termination are not immune to challenge — recently, an abortion performed at more than 24 weeks of gestation because of a cleft lip and palate was legally challenged by a trainee vicar who discovered it as she studied abortion statistics, though the physicians were ultimately not charged with a crime5 — but the absence of a time limit on some terminations of pregnancy is at odds with the strict limits for protecting the embryo in vitro.
It was a quirk in parliamentary procedure that allowed the "prolife" lobby to revisit the provisions of the 1967 Abortion Act during the debate on fertilization and embryology. The lobby succeeded in reducing the overall time limit for abortion from 28 weeks to 24 weeks, but not in cases in which the child could have serious mental or physical handicaps. These clauses now stand within the Human Fertilisation and Embryology Act.
The HFEA and the 1990 act that created it have served the British well and have provided a good model for regulation of assisted conception. But the act needs attention in this rapidly changing field, and the British government has indicated that it is under revision. It is also time for the government to remove the clauses of the Abortion Act that sit so uncomfortably within the Human Fertilisation and Embryology Act and to deal with the inconsistencies highlighted by the recent deliberations about PGD and susceptibility to disease.
Source Information
Prof. Braude is the head of the Department of Women's Health at King's College London, School of Medicine, London.
References
Human Fertilisation and Embryology Authority. (Accessed July 20, 2006, at http://www.hfea.gov.uk/cps/rde/xchg/SID-3F57D79B-DA4AC4C5/hfea/hs.xsl/1124.html.)
Rechitsky S, Verlinsky O, Chistokhina A, et al. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online 2002;5:148-155.
HFEA consultations. (Accessed July 20, 2006, at http://www.hfea.gov.uk/cps/rde/xchg/SID-3F57D79B-DA4AC4C5/hfea/hs.xsl/380.html.)
Renwick PJ, Trussler J, Ostad-Saffari E, et al. Proof of principle and first cases using preimplantation genetic haplotyping -- a paradigm shift for embryo diagnosis. Reprod Biomed Online 2006;13:110-119.
Meikle J. Cleft lip abortion done `in good faith.' Guardian. March 17, 2005. (Accessed July 12, 2006, at http://www.guardian.co.uk/uk_news/story/0,3604,1439312,00.html.)(Peter Braude, M.B., B.Ch.)