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Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients

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20 pages
The autosomal-dominant precancerous condition familial adenomatous polyposis (FAP) is caused by germline mutations in the tumour suppressor gene APC . Consistent correlations between the site of mutations in the gene and clinical phenotype have been published for different patient groups. We report our experiences of APC mutation analysis and genotype-phenotype correlations in 1166 unrelated polyposis families and discuss our results in the light of literature data. We show that the mutation detection rates largely depend on the family history and clinical course of the disease. We present a list of 315 different point mutations and 37 large deletions detected in 634 of the 1166 index patients. Our results confirm previously published genotype-phenotype correlations with respect to the colorectal phenotype and extracolonic manifestations. However, 'exceptions to the rule' are also observed, and possible explanations for this are discussed. The discovery of autosomal-recessive MUTYH -associated polyposis (MAP) as a differential diagnosis to FAP implies that some results have to be reinterpreted and surveillance guidelines in the families have to be reevaluated.
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Hereditary Cancer in Clinical Practice 2005; 3(3) pp. 95-114
Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients Waltraut Friedl, Stefan Aretz Institute of Human Genetics, University of Bonn, Germany
Key words: familial adenomatous polyposis, APC gene, APC mutations, genotype -phenotype correlations
Corresponding author: Dr. Waltraut Friedl, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany, phone +49 (0) 228-287-2334, fax +49 (0) 228-287-2380, e-mail: waltraut.friedl@ukb.uni-bonn.de
Submitted: 29 August 2005 Accepted: 2 September 2005
Abstract The autosomal-dominant precancerous condition familial adenomatous polyposis (FAP) is caused by germline mutations in the tumour suppressor gene APC . Consistent correlations between the site of mutations in the gene and clinical phenotype have been published for different patient groups. We report our experiences of APC mutation analysis and genotype-phenotype correlations in 1166 unrelated polyposis families and discuss our results in the light of literature data. We show that the mutation detection rates largely depend on the family history and clinical course of the disease. We present a list of 315 different point mutations and 37 large deletions detected in 634 of the 1166 index patients. Our results confirm previously published genotype-phenotype correlations with respect to the colorectal phenotype and extracolonic manifestations. However, 'exceptions to the rule' are also observed, and possible explanations for this are discussed. The discovery of autosomal-recessive MUTYH -associated polyposis (MAP) as a differential diagnosis to FAP implies that some results have to be reinterpreted and surveillance guidelines in the families have to be reevaluated.
Introduction that plays a major role in controlling cell cycle progression, migration, differentiation and apoptosis Familial adenomatous polyposis (FAP, OMIM (review in [4, 5]). Germline mutations in the APC gene +175100) is a clinical diagnosis that is typically based were also detected in some families with an attenuated on the presence of more than 100 colorectal adenomas. polyposis phenotype (AAPC, AFAP) who present with If untreated patients develop colorectal cancer at a mean less than 100 adenomas and a later age at onset age of 40 years [1]. Other gastrointestinal features compared to patients with typical FAP [6]. (duodenal adenomas, fundic gland cysts) and During the last few years correlations between site extragastrointestinal manifestations, including congenital of mutation in the APC gene and clinical phenotype hypertrophy of the retinal pigment epithelium (CHRPE), have been reported on patient groups of different sizes desmoids and osteomas are frequently described. [7-12]. Most of the published correlations proved to FAP is an autosomal-dominant disorder caused by be statistically consistent, but there were also 'deviations germline mutations in the tumour suppressor gene APC from the rule' when individual cases were considered. on chromosomal region 5q22 [2, 3]. The APC gene Recently a polyposis syndrome characterised by encodes a multifunctional protein of 2843 amino acids multiple adenomatous polyps and an autosomal-
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-recessive mode of inheritance has been identified that an atypical course usually presented with more than 100 is caused by germline mutations in the base excision polyps, diagnosed between 35 and 45 years of age; in repair gene MUTYH ( MYH ) [13]. Biallelic MUTYH addition, cases with an obvious discrepancy between mutations have been identified in up to 40% of patients the age at diagnosis (symptoms) and the number of in whom no mutation in the APC gene was identified colorectal adenomas were also considered atypical. If [14-16]. This new adenomatous polyposis condition is clinical information on the colorectal disease was not designated as MUTYH -associated polyposis (MAP; available or not sufficient to determine the extent of OMIM #608456) and has to be considered as colorectal polyposis, the phenotype was considered a differential diagnosis of the autosomal-dominant FAP. 'unknown'. In this review we report on our experience of mutation analysis in the APC gene and genotype-phenotype Family history correlations in 1166 unrelated patients with a clinical diagnosis of FAP or multiple adenomatous polyposis Due to the existence of the recent iscovered  consistent with AAPC and discuss our results in the light MUTYH -assoc 3 we ly d of literature data. important to aillaotewd f opr otlhyep omsios d[e1 of] inherciotannsicdee irne dth iet families: index patients were classified as familial cases Phenotype classification with autosomal-dominant inheritance when at least two patients (one of them a parent of the index patient) were Since 1991, blood samples from 1166 unrelated affected in the family. An autosomal-recessive mode of patients with a clinical diagnosis of typical or attenuated inheritance was considered when the index patient had FAP (AAPC) have been referred to the Institute of at least one affected sibling, but no affected parents or Human Genetics, University of Bonn for mutation children. Cases where the index patient was the only analysis in the APC gene. Clinical information on 2066 affected person known in the family, or no information patients from the 1166 families was obtained during on other family members (parents, siblings, children) was genetic counselling sessions, from a questionnaire, or available, were classified as 'single cases'. Index patients through telephone interviews and/or medical records. were classified as de novo mutations only if an APC The study was approved by the Ethics Commission of mutation was identified and both parents were either University Hospital, Bonn. healthy until an advanced age, or when the mutation was excluded in both parents, irrespective of whether or Colorectal phenotype not the index patient had affected children [17]. The classification of different FAP phenotypes was Mutation analysis in the APC gene based on the number of colorectal adenomas, age at diagnosis of FAP and occurrence of CRC (Table 1). The Point mutations FAP phenotype was classified as typical when the patient presented with more than 100 colorectal adenomas Genomic DNA extracted from peripheral blood before the age of 35; in cases of unavailable or unclear samples was used for mutation analysis. We started the colonoscopic data, the classification was based on the search for germline mutations in the APC gene in 1991 occurrence of clinical bowel symptoms before the age by SSCP and heteroduplex analysis. To date, we apply the of 35, or a diagnosis of CRC before the age of 45. The protein truncation test (PTT) for detection of mutations in diagnostic criterion for the attenuated phenotype (AAPC) exon 15 in four overlapping fragments, essentially as was the occurrence of a smaller number of adenomas described [18], using an in vitro transcription translation (10-100) after the age of 25 or more than 100 kit (Promega, Mannheim, Germany) in the presence of adenomas diagnosed for the first time after the age of 35 S-Methionine (Amersham). Denaturing high-performance 45. When the polyp number was unknown, AAPC was liquid chromatography (DHPLC) is used for screening of assigned if the first symptoms or diagnosis of CRC exons 1-14 and the first 400 bp of exon 15 (WAVE, occurred after the age of 45. The phenotype was Transgenomics). PCR fragments showing variant bands considered severe in patients who developed more than by either method were sequenced on an ABI prism 377 a thousand adenomas or polyposis-related bowel or ABI 3100 automated sequencer (Applied Biosystems, symptoms before the age of 15, or when diagnosed with Darmstadt, Germany) using the cycle sequencing polyps before the age of 10. The phenotype was procedure and the BigDye terminator kit version 2.0 or classified as atypical in patients who did not meet the 1.1, respectively. Some of the APC mutation negative criteria for either typical or attenuated FAP, when an patients from the first series were reexamined using the unambiguous attribution was impossible. Patients with more up-to-date procedures described.
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