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.
The authors provide a timely introduction to the use of predictivetesting as an adjunctive service in the management of a precancerouschronic disease, familial adenomatous polyposis (FAP). As theypoint out, this new technology carries a significant burden forboth the caregiver and affected family since it will alter thegenetic counseling process, as well as the clinical recommendationsfor managing FAP. The unique perspective of registry-based researchillustrates the value of generational study of a genetic anomalyover a 22-year-period.
Genetic counseling for FAP is a multifaceted process to assistfamilies in making autonomous, informed decisions, based on theirunderstanding of medical/genetic facts, available resources, andthe psychological impact of the diagnosis. The authors raise someprovocative issues related to the transfer of information fromcaregiver to patient, within the framework of a bench-to-bedsideapproach to FAP: ie, the testing of minors, limitations of genetesting, and interpretation of genetic test results.
The advent of presymptomatic diagnosis over the past 4 years hasprovided affected families with an alternative previously deniedthem. Despite the finding of genetic heterogeneity, the proportionof families with gene mutations that are not linked to the APClocus is still unknown. Up to 80% of individuals may benefit fromnewer techniques, such as the in vitro synthesized-protein assay,whereas a combination approach with direct mutation and linkageanalysis may be viable for other families. Furthermore, DNA maynow be extracted from available archival tissue specimens of keydeceased patients to determine carrier risk status in nuclearfamilies . In fact, FAP may serve as a model for colorectalcancer in the general population since somatic mutations of theAPC gene have been characterized in sporadic colonic tumors.
According to the authors, the variable age of onset of FAP requiresan expensive and lengthy surveillance regimen for first-degreerelatives. Their economic burden may involve travelling cost,time off from work, and debt when insurers refuse to cover biennialbowel examination. The emotional burden of screening for essentiallycovert disease from puberty onward often translates into noncomplianceby adolescents and young adults. Risk assessment, based on life-tableanalyses, does little to control for the variable FAP phenotype.Consequently, the role of genetic counseling in FAP is often determinedby timing, specifically, around diagnosis; childbearing; onsetof screening for offspring; and, now, performance of predictivetesting.
Family Dynamics Plays a Major Role
The coping ability of the newly diagnosed patient often hingeson that of other affected relatives. Family dynamics may playa major role if family identity is bound up with disease status.Historically, the absence of early bowel symptoms resulted inup to a 90% mortality in FAP, and many family members perceivedtheir risk as being close to l00%. Risk counseling may be ignoredif it conflicts with the family experience and does not addressemotional blocks.
The authors note that approximately 30% of patients with FAP areisolated cases, presenting with more advanced disease at a laterage, when their offspring may already be adults and thereforedenied the option of early clinical screening. Isolated caseslack the family history to ease acceptance of the diagnosis orthe genetic legacy borne by offspring. The manner in which riskdata are framed may alter the individual's ability to cope withthe conflict between scientific fact and subjective reality.
Reproductive issues are complicated by the recognition of FAPas an adult-onset disease. The lack of an acknowledged standardmay stimulate quality-of-life vs wrongful-life concerns. Colorectalcancer mortality has sharply declined in FAP, and emphasis hasnow shifted to chronic care of extracolonic manifestations. However,major bowel surgery remains the optimal treatment for a diseasewithout current cure. Discussion about the reasons for prenataldiagnosis or pregnancy termination may be integral to decision-making for affected couples, underscoring the need for referralto a geneticist or genetic counselor. One of the benefits of affiliationwith a registry is access to specialty services, either locallyor through teaching hospitals.
Puberty is a developmental stage characterized by increased physiologicchange and heightened awareness of body image. Many adolescentsperceive bowel examination as invasive and will not comply withongoing surveillance. For parents, this process may reinforcelatent fears, as indicated in a recent adaptation study, in whichmany parents expressed guilt about potentially transmitting theFAP 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 predictivetesting by citing the case of a recently widowed parent who requestedtesting for her three children, the youngest of whom was 7 yearsold. The lag time between a genetic and a clinical diagnosis needsto be considered for the very young. In the past, the diagnosisin at-risk offspring of extracolonic manifestations, such as epidermoidcysts and pigmented retinal lesions, prompted earlier investigation.In FAP, adenomas rarely, if ever, develop before puberty, negatingclinical intervention. Does the principle of beneficence overrideparental concern? One might speculate about the ability of a childto make a truly informed decision and about the need to recognizediffering reasoning levels between the very young, preadolescents,ado lescents, mature minors (equal to or more than 14 years oldwith autonomy as defined by local legislation), and emancipatedminors (adolescents living on their own and able to support themselves). By the same token, surveillance for FAP does beginat puberty. Thus, many FAP registries have adopted a policy ofoffering genetic testing at the onset of bowel screening.
Illustrating the problem of test limitations, the authors describethe case of two never-examined siblings in their 20s with offspringof their own. After both agreed to screening, one sibling wasdiagnosed with FAP and did not pursue molecular confirmation whilethe other had negative clinical and gene tests. Outside a researchsetting, a commercial laboratory might well have mailed moleculartest results, obviating the opportunity for pre- or post-testcounseling about the implications for each sibling or their progeny.Furthermore, there would not have been any recommendation forbaseline bowel examination.
The final case study highlights the hazards of caregivers nottrained in the subtleties of genetics and yet providing geneticcounseling. Unfortunately, the increased demand for genetic skillshas already outstripped the existing supply of counselors in manyhealth-care settings. However, for FAP, the primary-care clinicianmay refer affected families to one of 52 international registriesby contacting established centers or the regional Cancer Society.
Impact of Predictive Testing
The impact of predictive testing in FAP will become evident asscreening intervals are tailored for high- and low-risk individuals.The caveat about prophylactic colectomy in the presence of discernibledisease will become more significant as alternative therapiesevolve. A European chemoprevention trial is assessing resistantstarch and low-dose aspirin in APC gene-positive adolescents whohave been diagnosed with FAP but not yet treated . Such patientswill face potential insurance discrimination, although the workinggroup of the Ethical, Legal, and Social Implications (ELSI) ofHuman Genome Research has requested a moratorium on gene testingin underwriting.
More education, both in industry and academia, is required. Thisregistry report, and others to follow, will provide the geneticsand oncology community with prospective data about an adult-onsetcondition for which, unlike Huntington's disease, secondary preventionis feasible.
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