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

Institute of Human Genetics, University of Bonn, Germany. .
Hereditary Cancer in Clinical Practice (Impact Factor: 1.47). 09/2005; 3(3):95-114. DOI: 10.1186/1897-4287-3-3-95
Source: PubMed


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.

Full-text preview

Available from: PubMed Central
  • Source
    • "Susceptibility to FAP is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Some 20% of classical FAP and 70% of AFAP cases remain APC mutation-negative (Friedl and Aretz, 2005). This may be due to APC alterations that go undetected (Aretz et al., 2007; Spier et al., 2012), nontruncating APC alterations whose pathogenic significance is difficult to interpret (Aretz et al., 2004), or predisposing genes other than APC, such as MUTYH (Sieber et al., 2003) and AXIN2 (Lammi et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 10/2014; 53(10). DOI:10.1002/gcc.22197 · 4.04 Impact Factor
  • Source
    • "The first deletion, found in the FAM1, results in the loss of two bases (eAA) in codon 1062. Although rarely reported [13] this deletion overlaps with a mutational hot-spot of the FAP syndrome, codons 1062 and 1063, and involves the binding site for betacatenin [14]. Interestingly, we learned that the individual, examined in Gismondi's study and carrying the same deletion, was of Sicilian origin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: a b s t r a c t Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported. In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment. We have detected different APC mutations in these five pedigrees, confirming the remarkable het-erogeneity of the mutational spectrum in FAP.
    International Journal of Surgery (London, England) 06/2014; 12 Suppl 2. DOI:10.1016/j.ijsu.2014.08.365 · 1.53 Impact Factor
  • Source
    • "A study of over 100 Dutch families revealed equal frequency of those two most frequent mutations (3927–3931delAAAGA and 3183–3187delACAAA) [10]. The largest studies of APC gene mutations were performed on a German population [11,12]. The latest published report in 2005 involved the analysis of over 1000 patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.
    Hereditary Cancer in Clinical Practice 02/2007; 5(4):195-8. DOI:10.1186/1897-4287-5-4-195 · 1.47 Impact Factor
Show more