GASTROENTEROLOGY

1991;100:1658-1664

Screening Guidelines and Premorbid Diagnosis of Familial Adenomatous Polyposis Using Linkage GLORIA

M. PETERSEN,

JOAN

SLACK,

and YUSUKE

NAKAMURA

Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center, UCLA School Los Angeles, California; Clinical Genetics Department, Royal Free Hospital, School London, England: and Division of Biochemistry, Cancer Institute, Tokyo, Japan

Restriction fragment-length polymorphisms in the chromosome 5q21-22 region can now he used clinically for premorbid diagnosis and counseling in familial adenomatous polyposis. Two families are presented in which DNA diagnosis for familial adenomatous polyposis was performed using linked restriction fragment-length polymorphisms. Screening guidelines are improved using data from the polyposis registers at St. Mark’s Hospital (London) and Western Australia (Perth) on at-risk family members who subsequently developed familial adenomatous polyposis. In these registers, 103 of 137 relatives tested positive on initial screening; of the remaining 34, the average interval between initial negative screening and development of familial adenomatous polyposis was 7.5 years. All those who had inherited the familial adenomatous polyposis gene manifested the polyps by age 34 years. Combined with linkage marker data, the a priori 50% risk for relatives can now be reduced to < 0.5% by age 30 years if there is an initial negative result on sigmoidoscopy and a negative diagnosis by linkage analysis. The screening management for those found by linkage to have inherited familial adenomatous polyposis remains unchanged from established recommendations; however, for individuals who most likely have not inherited familial adenomatous polyposis, the clinician can emphasize the positive aspects of screening management, including longer screening intervals. amilial adenomatous polyposis (FAP), synonymous with adenomatous polyposis coli or familial polyposis coli, is an inherited autosomal dominant condition with high ( > 90%) penetrance (l-6). It is characterized by multiple (> 100) adenomatous polyps in the colon and rectum; variant features in addition to the colonic polyps include polyps in the

F

of Medicine, of Medicine,

upper gastrointestinal tract and extraintestinal manifestations, including osteomas and epidermoid cysts, desmoid formation, congenital hypertrophy of retinal pigment epithelium, and other malignant changes such as thyroid tumors (l-9). Gardner’s syndrome, which includes the extraintestinal features, is a clinical and genetic variant of FAP (8,10,11). There is virtually 100% risk of colon cancer in persons who inherit the FAP gene and manifest the adenomatous polyps (1-5). Offspring of an affected individual are at 50% risk of inheriting the condition. Based solely on the recognized mode of inheritance, screening management of at-risk relatives has consisted of annual colon examinations by endoscopy beginning around puberty. The objective of this regimen is early identification of those who have inherited the gene, to whom preventive colectomy is advised. In fact, the risk of malignant change in the lower gastrointestinal tract is so high that elective ileorectal anastomosis is usually performed when colorectal polyposis has been identified (3-5,9). The clinical manifestations and age at onset of first symptoms in FAP are variable, even within families. The ideal age to start screening children at risk and the most appropriate age to stop screening at-risk adults who have not yet manifested the condition are still a matter of debate (2,12,13). Of particular relevance in developing optimal screening guidelines is the variable age of FAP symptom onset and diagnosis. A survey of 281 FAP patients who presented with and were diagnosed based on symptoms shows a wide range in age at diagnosis, from 4 to 73 years, with a

Abbreviations used in this paper: FAP, familial adenomatous polyposis; RFLP, restriction fragment-length polymorphism. Q 1991 by the American Gastroenterological Association 0016~5065/91/$3.00

GENETIC COUNSELING

June 1991

mean age of 35.8 years (3). However,

these data are not applicable when considering appropriate screening guidelines for relatives who are already known to be at 50% risk. Bussey et al. (7) noted that the range of age at diagnosis among at-risk (“call-up”) relatives was 8-57 years, with an average of 23.8 years. In 75% percent of this group, FAP is diagnosed before age 30. More recently, among 357 offspring screened for polyps from 1951 to 1987 in the St. Mark’s Hospital program, 34.7% were found on first screening to have polyps, but in the two thirds of those in whom FAP was not diagnosed at first screening it was diagnosed by age 20 years (12). These observations are more appropriate for developing screening regimens for at-risk relatives. Moreover, accurate FAP genetic diagnosis in families will also affect screening guidelines. Until identification of the FAP gene itself becomes a reality, a large number of restriction fragment-length polymorphisms (RFLPs) in the region near the FAP gene will make premorbid diagnosis possible through linkage analysis (11,14-l 7). Linkage principles have long been used by geneticists to refine probabilities of disease inheritance in family members who are at risk for genetic disorders (18,19). Linkage analysis uses the fact that two physically proximate genetic loci will tend to be transmitted together from parent to offspring more frequently than if the loci were independently assorting during meiosis. The amount of information available for molecular diagnosis using linkage analysis is dependent on the pedigree structure, the number of available RFLP markers tightly linked to the FAP gene locus, and their relative frequencies in the population. With the array of molecular probes in the chromosome 5q21-22 region now available, it is likely that most pedigrees in which FAP is segregating will be informative. Familial adenomatous polyposis linkage markers give us the opportunity to refine the probability that a family member at 50% risk for FAP will be affected when he or she has no visible polyps on sigmoidoscopy by a given age. We have analyzed a linked RFLP marker in two FAP families, the first such clinical application for premorbid diagnosis. However, we also must modify the screening recommendations when such diagnoses are known. We used observations from the St. Mark’s and Perth FAP registers to develop suggested screening guidelines. Case Reports Family 1 (Figure 1A) The index case [III-2) is a 36-year-old father currently asymptomatic children, all under age 10. proband, FAP was diagnosed upon screening at age underwent a subtotal colectomy with rectal sparing

of four In the 11. He at age

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17. Multiple adenomas in the rectal stump are removed during the course of regular screening. A family history of PAP on his father’s side is evident: the cause of death of his paternal grandmother (I-l) was reported to be colon cancer, his paternal uncle (11-3) had FAP and died of colon cancer around age 40, and his father (II-2), who also had FAP, died of colon cancer at age 33. His asymptomatic 35-year-old brother (111-3) has been screened since age 6 and has no evidence of polyps. Without information from linkage analysis, all children (IV-l to IV-4) have a 50% risk of developing FAP. None has yet been screened for colonic polyps.

Family 2 (Figure 2) The index case (111-2) and her sister had FAP diagnosed by conventional screening at ages I4 and 12 years, respectively, before entry into our study. Their father (11-2) died of colon cancer at age 30, although FAP was diagnosed when he was a teenager. His father [I-l) also had FAP and died of colon cancer at age 33. Their asymptomatic brother (III-l] has been screened annually for colonic polyps since age 5, with consistently negative results. His most recent colonoscopy was this year at age 25. Based on conventional genetic empiric risk figures alone, he remains at 50% risk of developing FAP.

Empiric Risk Analysis and Results A total of 345 families were registered in the St. Mark’s and Perth FAP registers at the time of our study. Careful examination of the records in the St. Mark’s polyposis register showed that the most consistent screening procedure used was rigid sigmoidoscopy, although barium enema or colonoscopy occasionally diagnosed the appearance of polyps earlier than sigmoidoscopy. The diagnosis in the great majority was made by rigid sigmoidoscopy. From the registers, we obtained complete information for the empiric risk analysis on a sample of 137 family members who had a prior probability of 50% and subsequently developed FAP. The probabilities of finding polyps at first screening in these relatives who have inherited the gene can be estimated from this sample. The probability of finding polyps is 15% at age 10 years but increases to 82% at age 15,94% at age 20, and 98% at age 30. Of the 137 relatives, 103 were found to be affected at the first screening. Therefore, the age at which polyps actually developed can be estimated only from the relatives who attended one or more times previously with negative screening results and were subsequently found to have polyps. Thirty-four patients from the two registers were found to have negative screening results at a previous examination but subsequently developed polyposis. The initial negative screening and diagnosis of FAP were performed by rigid sigmoidoscopy. The midpoint between the first

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PETERSEN

ET AL.

GASTROENTEROLOGY

Vol. 100, No. 6

II

Figure 1. Family 1.

?? , 0, FAP; probe, EF5.44; enzyme, Msp I.

A. With the linkage information, we could and the youngest child (IV-4) did inherit polyposis gene.

counsel the family with > 98% confidence the polyposis gene. In this family, allele

that the three oldest children 1 of the EF5.44 gene marker

were not at risk for FAP is segregating with the

E. Southern blot results showing genomic DN.4 digested with Msp I and probed with EF5.44. Lanes are labeled to correspond of pedigree in A. Lane d contains DNA from an unrelated individual. Lane j contains the fragment size standards. Allele fragment, and allele z is the 2.0-kb fragment.

positive and the last negative screening was taken as the best estimate of age at which polyps developed. The mean age of the relatives at their last negative screening was 14.1 f 5.6 (SD) years. The mean time interval between negative and positive screening was 7.5 years, with a range of l-11 years. The estimated mean age at onset of FAP in the sample of 34 relatives is 15.9 f 5.4 (SD) years. In Figure 3, the cumulative curve a illustrates the probability of finding polyps at a given age if the

with members 1 is the 2.3.kb

individual has inherited the FAP gene. The probability rapidly rises between the ages of 10 and 20 years, and in our series all those affected had developed polyps by age 34. Curve b of Figure 3 illustrates the probability that a relative at 50% risk will be affected with FAP if the results of a previous sigmoidoscopy screening were negative. Until age 10 years, there is a very small diminution in risk, with 49% probability. The risk falls rapidly between ages 14 and 20 years to 20%, and is only 8% by age 30.

GENETIC COUNSELING

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Table 1. Bayesian Probabilities That a Relative at 50% Risk for Familial Adenomatous Polyposis Has Inherited the Gene

I

-

Probability if linked marker is at 5% recombination distance Probability if linked marker is at 2% recombination distance

II

Age at screening

10yr

15yr

2OYr

30yr

2.4%

1.5%

1.0%

0.4%

1.0%

0.6%

0.4%

0.2%

NOTE. We assume that the relative has had a prior negative sigmoidoscopic screening result and that results of the linkage test are negative (i.e., he or she does not have the marker linked to the FAP gene).

tl 1 25 YRS

III

2-2

24 YRS DX:

LYRS

22 YRS DX:lt:

YRS

Figure 2. Family 2. With the linkage information, we could counsel tbe family that the risk of FAP in tbe brother (III-l) was 3.0 with no recombination (11). Linkage analysis using this marker enables identification of individuals who have inherited the FAP gene within a pedigree, by comparison of the genotypes of the linked marker in individuals known to have the gene with individuals without the gene. Family 1. As seen in Figure lA, we could infer that the FAP gene was linked to allele 1 of the EF5.44 marker because the index case (111-2) inherited allele 2 from his mother. This is reinforced by the 2-2 phenotype of his brother, 111-3, who has manifested no evidence of inheriting the FAP gene. We counseled the family that the first three children probably did not inherit the polyposis gene and that the youngest child did inherit FAP, with more than 98% confidence. Family 2. From the DNA studies on the index case and her sister (III-2 and III-3), as seen in Figure 2, we could conclude that the FAP gene was also linked in this family to allele 1 of the EF5.44 marker. The important issue in this family is the appropriate counseling for their brother, III-l. In the absence of genetic linkage information, his risk of having inherited the FAP gene is reduced from 50% to < 10% based on his age and the negative screening results (Figure 3b). However, when we incorporate the information from the gene marker data, this risk drops to

Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage.

Restriction fragment-length polymorphisms in the chromosome 5q21-22 region can now be used clinically for premorbid diagnosis and counseling in famili...
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