Genetic Testing and Counseling in Familial Adenomatous Polyposis

Introduction

Over the past decade, we have made major discoveries about the molecular genetic basis of colorectal cancer, including the identification of genes that cause certain colorectal cancer syndromes [1-4]. There is little doubt that these discoveries will lead not only to a better understanding of etiology but also to improvements in the clinical management of colorectal cancer patients and their families.

One of the best examples of how basic research has made the transition to clinical application is in familial adenomatous polyposis (FAP). As a result of the discovery and characterization of the gene for FAP, predictive genetic testing can now be offered to family members in FAP kindreds [5]. However, the new technology carries an important responsibility for the clinician to help at-risk individuals who may choose genetic testing to understand the implications of the test.

We will briefly review the genetics of FAP, and discuss the various issues related to the genetic counseling and management of FAP patients, at-risk persons, and their families. Our paper represents a body of experience drawn from work with families in the FAP registry at The Johns Hopkins Hospital [6]. The Hopkins registry, which originated in 1973, has followed hundreds of FAP patients from over 300 families, many of them large and multigenerational. We will present several case reports to illustrate the breadth of the issues that may arise in the context of predictive genetic testing for FAP.

Genetics of FAP

The clinical features of FAP have been well documented [7-9]. As its name implies, familial adenomatous polyposis is a condition characterized by numerous adenomatous polyps (100) in the colon, which exhibits autosomal dominant inheritance in families. This means that affected persons are heterozygous, such that each offspring of a patient with FAP has a 50% chance of inheriting the disease gene. The gene responsible for FAP is known as APC (for adenomatous polyposis coli) and is located on chromosome 5q2l [1-2,10].

Mutations of the APC gene have been found in patients with FAP (eg, 2,11). These are often insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. It is not yet clear how the subsequent truncated protein product causes adenomas to form. Capitalizing on the nature of these mutations, however, has led to the development of a molecular genetic test for FAP [12]. Unlike genetic linkage analysis, this test is useful with spontaneous, or "new mutations" (the first occurrence of FAP in a kindred), which may account for as many as one-third of incident cases [7-9].

Genetic and Clinical Heterogeneity

Recent evidence suggests that there is genetic heterogeneity of FAP. Several kindreds have been described that do not appear to be linked to the gene region on chromosome 5q [13]. Also, in some FAP patients, there has been an apparent inability to detect APC mutations [12,14].

On the other hand, clinical variability of FAP has been manifested by the appearance of the adenomas in some families that do have an APC mutation. A variant entity of FAP with attentuated polyps has been called the hereditary flat adenoma syndrome [15,16], and in the reported kindreds appears to be due to mutations in the APC gene. Other workers have suggested, however, that diminutive adenomas will progress to larger, ordinary adenomas [17].

Conventional Management of FAP

Individuals who inherit a mutant APC gene have a very high likelihood of manifesting colonic adenomas; penetrance has been estimated to be over 90% [7-9]. The age at onset of adenomas in the colon is variable. Cumulative age-at-onset curves suggest that by age 10 years, only 15% of FAP gene carriers manifest adenomas; by age 20, the probability rises to 75%; and by age 30, 90% will have presented with FAP [7-9,18].

Without any intervention, most persons with FAP will inevitably develop colon or rectal cancer by 40 years of age. Thus, the medical goal in patients with FAP is to prevent colon cancer. Conventional management of persons at 50% risk of developing FAP has been to initiate annual colon surveillance by flexible sigmoidoscopy in late childhood and to perform subsequent colectomy when numerous polyps are present [19,20]. While it is not unusual to find FAP patients under age 12 who have dozens of polyps, colon cancer has been reported in children as young as 10 years of age [7-9]. Under no circumstances, however, is preventive colectomy indicated in FAP patients prior to the appearance of polyps.

Contexts of Genetic Counseling

Genetic counseling of FAP patients and their family members can occur in several contexts: at the time of diagnosis of FAP, at the time that an FAP patient is considering reproductive options, at the time that the FAP patient is having his or her children screened, and at the time that an at-risk person is considering genetic testing. In the following sections, each of these contexts will be discussed in light of new information and risks that can be conveyed during counseling at that particular time.

When FAP Is Diagnosed

This is the most common, conventional context in which FAP patients are told about the condition and its genetic implications. Not only are these patients coping with the disease and its medical implications, they are also told that it is hereditary and that their offspring may inherit the condition. For newly diagnosed patients, this can be the most stressful time, as they deal with the clinical sequelae, medical tests, and eventual surgery. Often, patients with "new mutations" may have been diagnosed when symptoms and possibly colon or rectal cancer have presented. Thus, they may not be ready to absorb the genetic implications of FAP until they have dealt with the requisite medical procedures.

Genetic counseling of newly diagnosed FAP patients and their families is essential. Since many patients may be learning for the first time about the hereditary nature of FAP, referral to a clinical geneticist or genetic counselor is optimal, although we have observed that this often does not occur in practice. The genetic counselor obtains detailed information about the family history, including health and cancer histories of blood relatives; family structure; and social support within and outside the immediate family. Once this information has been collected, pedigrees are drawn and recurrence and other risks assessed.

Genetic counseling generally serves two functions: (1) to help the patient and family understand medical and genetic information about FAP, and (2) to provide emotional and psychological support as the family copes with the new information and burdens that such information can impose. This process is best accomplished by a series of discussions over time. Because so much has been learned about the genetic basis and management of FAP, patients can be given reasons to be hopeful about future prospects in prevention and treatment of this condition.

When Starting or Continuing a Family

Increasingly more often, FAP patients are being diagnosed in late childhood or adolescence [7,20]. When such patients mature and decide to start their own family, the genetic counselor or health professional needs to review and discuss with both the patient and his or her partner many of the issues related to inheritance and the latest technological developments. Specific issues to be reviewed include the mode of inheritance of FAP, the recurrence risk for offspring, and the fact that the risk of FAP for each offspring is independent of the others.

After a careful, sensitive exploration and discussion of the goals, values, and wishes of the couple, reproductive options can be sifted, including the feasibility of prenatal genetic diagnosis, adoption, and artificial insemination. Prenatal genetic diagnosis of FAP is a technically feasible option, as is in vitro preimplantation diagnosis, but neither has ever been performed, to the authors' knowledge. Anecdotally, during the course of pregnancy, several couples have inquired about prenatal genetic diagnosis, but after thinking through the consequences (ie, what would they do should the gene test indicate that the fetus had inherited the mutant APC gene?), this option was not elected. These experiences underscore the importance of careful, thoughtful discussion of all the issues.

A related, but different situation occurs when a couple may already have one or two children and wish to have more, but the decision depends on whether those already born have inherited the FAP gene. Couples may have different, often valid rationales for seeking this information about children who may be quite young and for whom intervention may be years away. These reasons may include burden of caretaking, insurance coverage, or financial obligations for which the couple may want to appropriately plan.