The authors provide a timely introduction to the use of predictive testing as an adjunctive service in the management of a precancerous chronic disease, familial adenomatous polyposis (FAP). As they point out, this new technology carries a significant burden for both the caregiver and affected family since it will alter the genetic counseling process, as well as the clinical recommendations for managing FAP. The unique perspective of registry-based research illustrates the value of generational study of a genetic anomaly over a 22-year-period.
Genetic counseling for FAP is a multifaceted process to assist families in making autonomous, informed decisions, based on their understanding of medical/genetic facts, available resources, and the psychological impact of the diagnosis. The authors raise some provocative issues related to the transfer of information from caregiver to patient, within the framework of a bench-to-bedside approach to FAP: ie, the testing of minors, limitations of gene testing, and interpretation of genetic test results.
The advent of presymptomatic diagnosis over the past 4 years has provided affected families with an alternative previously denied them. Despite the finding of genetic heterogeneity, the proportion of families with gene mutations that are not linked to the APC locus is still unknown. Up to 80% of individuals may benefit from newer techniques, such as the in vitro synthesized-protein assay, whereas a combination approach with direct mutation and linkage analysis may be viable for other families. Furthermore, DNA may now be extracted from available archival tissue specimens of key deceased patients to determine carrier risk status in nuclear families . In fact, FAP may serve as a model for colorectal cancer in the general population since somatic mutations of the APC gene have been characterized in sporadic colonic tumors.
According to the authors, the variable age of onset of FAP requires an expensive and lengthy surveillance regimen for first-degree relatives. Their economic burden may involve travelling cost, time off from work, and debt when insurers refuse to cover biennial bowel examination. The emotional burden of screening for essentially covert disease from puberty onward often translates into noncompliance by adolescents and young adults. Risk assessment, based on life-table analyses, does little to control for the variable FAP phenotype. Consequently, the role of genetic counseling in FAP is often determined by timing, specifically, around diagnosis; childbearing; onset of screening for offspring; and, now, performance of predictive testing.
Family Dynamics Plays a Major Role
The coping ability of the newly diagnosed patient often hinges on that of other affected relatives. Family dynamics may play a major role if family identity is bound up with disease status. Historically, the absence of early bowel symptoms resulted in up to a 90% mortality in FAP, and many family members perceived their risk as being close to l00%. Risk counseling may be ignored if it conflicts with the family experience and does not address emotional blocks.
The authors note that approximately 30% of patients with FAP are isolated cases, presenting with more advanced disease at a later age, when their offspring may already be adults and therefore denied the option of early clinical screening. Isolated cases lack the family history to ease acceptance of the diagnosis or the genetic legacy borne by offspring. The manner in which risk data are framed may alter the individual's ability to cope with the conflict between scientific fact and subjective reality.
Reproductive issues are complicated by the recognition of FAP as an adult-onset disease. The lack of an acknowledged standard may stimulate quality-of-life vs wrongful-life concerns. Colorectal cancer mortality has sharply declined in FAP, and emphasis has now shifted to chronic care of extracolonic manifestations. However, major bowel surgery remains the optimal treatment for a disease without current cure. Discussion about the reasons for prenatal diagnosis or pregnancy termination may be integral to decision- making for affected couples, underscoring the need for referral to a geneticist or genetic counselor. One of the benefits of affiliation with a registry is access to specialty services, either locally or through teaching hospitals.
Puberty is a developmental stage characterized by increased physiologic change and heightened awareness of body image. Many adolescents perceive bowel examination as invasive and will not comply with ongoing surveillance. For parents, this process may reinforce latent fears, as indicated in a recent adaptation study, in which many parents expressed guilt about potentially transmitting the FAP gene to their offspring . The authors caution that parents' information gaps or misperceptions may be mirrored in their offspring, especially when there are language or cultural barriers.
Case Studies Highlight Important Issues
The authors illustrate the question about when to initiate predictive testing by citing the case of a recently widowed parent who requested testing for her three children, the youngest of whom was 7 years old. The lag time between a genetic and a clinical diagnosis needs to be considered for the very young. In the past, the diagnosis in at-risk offspring of extracolonic manifestations, such as epidermoid cysts and pigmented retinal lesions, prompted earlier investigation. In FAP, adenomas rarely, if ever, develop before puberty, negating clinical intervention. Does the principle of beneficence override parental concern? One might speculate about the ability of a child to make a truly informed decision and about the need to recognize differing reasoning levels between the very young, preadolescents, ado lescents, mature minors (equal to or more than 14 years old with autonomy as defined by local legislation), and emancipated minors (adolescents living on their own and able to support themselves) . By the same token, surveillance for FAP does begin at puberty. Thus, many FAP registries have adopted a policy of offering genetic testing at the onset of bowel screening.
Illustrating the problem of test limitations, the authors describe the case of two never-examined siblings in their 20s with offspring of their own. After both agreed to screening, one sibling was diagnosed with FAP and did not pursue molecular confirmation while the other had negative clinical and gene tests. Outside a research setting, a commercial laboratory might well have mailed molecular test results, obviating the opportunity for pre- or post-test counseling about the implications for each sibling or their progeny. Furthermore, there would not have been any recommendation for baseline bowel examination.
The final case study highlights the hazards of caregivers not trained in the subtleties of genetics and yet providing genetic counseling. Unfortunately, the increased demand for genetic skills has already outstripped the existing supply of counselors in many health-care settings. However, for FAP, the primary-care clinician may refer affected families to one of 52 international registries by contacting established centers or the regional Cancer Society.
Impact of Predictive Testing
The impact of predictive testing in FAP will become evident as screening intervals are tailored for high- and low-risk individuals. The caveat about prophylactic colectomy in the presence of discernible disease will become more significant as alternative therapies evolve. A European chemoprevention trial is assessing resistant starch and low-dose aspirin(Drug information on aspirin) in APC gene-positive adolescents who have been diagnosed with FAP but not yet treated . Such patients will face potential insurance discrimination, although the working group of the Ethical, Legal, and Social Implications (ELSI) of Human Genome Research has requested a moratorium on gene testing in underwriting.
More education, both in industry and academia, is required. This registry report, and others to follow, will provide the genetics and oncology community with prospective data about an adult-onset condition for which, unlike Huntington's disease, secondary prevention is feasible.