Changing Our Genetic Legacy Is Possible – A Path to Stopping Hereditary Cancer

Genetic Predisposition Need Not Determine the Fate of Future Generations

Hereditary cancer predisposition syndromes (CPS) are associated with genetic mutations passed between generations, substantially increasing lifetime cancer risk. New medical technologies challenge the idea that this genetic legacy is inevitable. Advanced reproductive technologies such as preimplantation genetic testing (PGT) can prevent transmission of genetic predispositions to future generations. People carrying hereditary cancer mutations can now change this fate and build a healthy future. This article explores ways to manage genetic cancer risk and the role of PGT in hereditary cancers, particularly its critical contribution to prevention.

A Comprehensive Review of PGT Use and Public Awareness in Cancer Predisposition Syndromes

Cancer predisposition syndromes (CPS) are inherited genetic disorders that increase lifetime cancer risk and complicate reproductive decisions. Managing personal health and genetic risks passed to future generations is essential. PGT offers an important reproductive option by increasing the likelihood of having children without a hereditary cancer mutation. Awareness and acceptance remain limited among patients and health professionals, however. A study published in November 2023 in Genes (Basel) provides the basis for this review of public awareness and acceptance of PGT in CPS. We examine the literature in depth and discuss how clinical, ethical, psychological, and sociocultural factors influence the process.

NOTE:

Preimplantation Genetic Testing (PGT) detects genetic disorders in embryos created through in vitro fertilization (IVF). Identifying mutations or chromosomal abnormalities allows healthy embryos to be selected.

PGT-M is a type of preimplantation testing for monogenic diseases caused by a mutation in a single gene. Most hereditary cancers are single-gene disorders of this kind. The test aims to identify embryos carrying known familial genetic diseases, select unaffected embryos, and transfer them to the uterus.

How Is PGT-M Performed? The Technology

PGT-M (Preimplantation Genetic Testing for Monogenic Disorders) tests embryos created during IVF for genetic disease. The process involves:

1. Embryo Creation: Ovarian stimulation with hormones is followed by egg collection and laboratory fertilization with sperm. The fertilized egg (embryo) develops for several days.

2. Biopsy: When the embryo reaches the blastocyst stage after 5-6 days, a few cells are biopsied. This is performed without harming the embryo.

3. Genetic Analysis: The cells are sent to a genetics laboratory for analysis of specific mutations causing the monogenic disease. Embryos are analyzed to identify those unaffected.

4. Transfer of a Healthy Embryo: An embryo found genetically healthy is placed in the woman's uterus, and normal pregnancy begins.

This technology identifies embryos carrying known familial genetic diseases and allows healthy embryos to be selected.

Cancer Predisposition Syndromes: Understanding Genetic Risk

CPS result from inherited or newly arising (de novo) pathogenic mutations. They increase cancer susceptibility, often characterized by early onset and multiple tumors. Sporadic cancer arises from somatic mutations, whereas CPS involve inherited mutations and lifelong risk. Common features include:

• Early Tumor Development: For example, soft-tissue sarcomas can develop during childhood or early adolescence in Li-Fraumeni syndrome.
• Multiple Tumor Types: Syndromes such as neurofibromatosis can cause multiple tumors in the same person.
• Positive Family History: Most CPS are inherited in an autosomal dominant pattern, often producing similar cancer histories within families.

Autosomal Dominant Inheritance, the Two-Hit Hypothesis, and Cancer Genes

The Two-Hit Hypothesis: Knudson's hypothesis underlies cancer development in CPS. It proposes that both alleles of a tumor suppressor gene must be mutated for cancer to develop. One mutation is already present in the germline in people with CPS, and a second somatic mutation is highly likely, increasing tumor risk.

These concepts may appear contradictory, but they are not. Autosomal dominant inheritance means that disease risk can arise from a single mutated gene copy. The two-hit hypothesis applies particularly to tumor suppressor genes and proposes that both alleles must be mutated for cancer to develop.

Autosomal dominant hereditary cancer syndromes, such as those involving BRCA1/2 mutations, generally involve a germline mutation in one tumor suppressor gene copy. Knudson's two-hit hypothesis requires the second allele to be mutated somatically. The inherited mutation is only the first hit; cancer development requires another mutation or inactivation. A carrier has increased disease risk, but a second event is essential for cancer to develop.

Tumor Suppressors and Oncogenes: The two-hit hypothesis applies particularly to tumor suppressor genes, proposing that both alleles must be inactivated. For oncogenes, a single mutation may be sufficient for cancer to develop, demonstrating a different mechanism from tumor suppressor inactivation.

Thus, autosomal dominant inheritance is sufficient to transmit the disease, while cancer development often requires a second tumor suppressor mutation. The two-hit hypothesis helps explain this aspect of cancer biology.

The Clinical Importance of a CPS Diagnosis

A diagnosis has several clinical implications. It provides access to targeted screening for early detection and prompt treatment. Primary prevention is also possible for some syndromes. For example, in BRCA mutation carriers, prophylactic mastectomy (preventive breast removal) and oophorectomy (ovary removal) substantially reduce cancer risk. These procedures can improve lifespan and quality of life and have far-reaching effects on the family.

Because most CPS are autosomal dominant, affected individuals have a 50% chance of transmitting a mutation to their children. Genetic testing can therefore support similar preventive measures among relatives.

Reproductive Options: The Importance of PGT-M for Patients with CPS

PGT-M identifies monogenic disorders in IVF embryos, allowing unaffected embryos to be selected for uterine transfer. By avoiding traumatic processes such as invasive prenatal diagnosis and pregnancy termination, it offers a more ethical and acceptable option.

The first PGT-M cases involved highly penetrant CPS such as Li-Fraumeni syndrome and neurofibromatosis 1, offering an effective way to prevent genetic transmission.

Awareness and acceptance remain low, however, because of limited clinical knowledge, ethical debate, high costs, and psychological stress associated with the procedure.

Clinical Success Rates and Ethical Issues

Current evidence indicates that PGT-M in CPS achieves success similar to that in other genetic diseases, with high rates of successful pregnancy and live birth.

However, ethical debates about using PGT-M for cancer predisposition syndromes continue. Important issues include their tendency to develop late and their variable penetrance, and the availability of effective screening and treatment raise questions about applying PGT-M to these conditions.

NOTE:

Penetrance is the genetic term for the probability that an inherited gene causes disease in a carrier. The penetrance of hereditary cancer genes describes the proportion of mutation carriers who develop cancer during their lifetime. A highly penetrant gene causes cancer in most carriers. For example, certain subtypes of BRCA1 or BRCA2 mutations are highly penetrant, meaning a very high cancer risk. With low-penetrance genes, carriers have a lower probability of cancer.

Opponents of PGT-M for CPS cite later disease onset and available monitoring and treatment as key ethical concerns. For example, although a BRCA carrier has a high later-life cancer risk, penetrance varies and surveillance can manage risk. In contrast, PGT-M is considered more ethical and acceptable for highly penetrant syndromes linked to childhood cancer, such as Li-Fraumeni syndrome.

Awareness and Acceptability: Health Professional and Patient Perspectives

Studies show limited awareness in both groups. A 2012 meta-analysis found that only 35% of people with CPS knew about PGT-M. Even among those with greater awareness, personal willingness to use it remained low because of ethical concerns, cost, and the stress of medical procedures.

Health professionals also lack knowledge. A 2010 survey of gynecologists, genetic specialists, and oncologists found that 68% had limited or incorrect knowledge about PGT-M in CPS. However, 80% intended to refer patients to a specialist. This suggests recognition of knowledge gaps and efforts to guide patients appropriately.

Patient Acceptance and Influencing Factors

Acceptance varies by clinical and demographic characteristics. It is higher for early-onset, highly penetrant syndromes such as Li-Fraumeni and lower for late-onset, low-penetrance syndromes such as BRCA mutations. Acceptance is also higher among men than women, partly attributed to women's concerns about IVF hormone treatment.

Sociocultural and ethical factors also matter. Some people view preventing transmission to future generations as a responsibility, while others avoid the technology for religious or ethical reasons. Because PGT-M does not require pregnancy termination, many patients consider it more ethically and psychologically acceptable.

Conclusion: The Future Potential of PGT-M in CPS

In conclusion, PGT-M offers an important reproductive option for people with CPS, but awareness and acceptability require further research. Wider genetic testing is expected to increase CPS diagnoses and future demand for PGT-M. Multidisciplinary approaches are essential to managing the ethical, psychological, and clinical dimensions. Involving patients in decisions through genetic counseling, oncologic surveillance, and psychological support will help them make well-informed choices. Professional guidelines will also help clinicians provide reproductive counseling for patients with CPS.