Combined Molecular and Clinical Approaches for the Identification of Families with Familial Adenomatous Polyposis Coli

Abstract

ObjectiveUsing an interdisciplinary clinical and molecular approach, the authors identified APC germline mutations in families with familial adenomatous polyposis (FAP). Correlation of mutation site with disease manifestation and the impact of molecular data on clinical proceedings were examined. Summary Background DataGermline mutations in the APC gene predispose to FAP. Established and proposed genotype-phenotype correlations as well as the influence of mutation site on surgical procedures have been reported. The predictive value of APC mutation analysis for disease manifestation and therapeutic decision making needs to be investigated further. MethodsOne hundred twenty-three kindreds of the local FAP registry were included in this study. CHRPE phenotype was defined as at least one large charactenstic lesion or a total of four lesions in both eyes. APC mutations were identified by protein truncation test and automated DNA sequencing from patient Iyrphocyte DNA and RNA. ResultsAPC germline mutations were identified in 85/123 families with FAP. They were located between codons 213 and 1581 of the APC gene and displayed distinct genotypephenotype correlations. CHRPE status facilitated mutation analysis by discriminating regions of interest within the APC coding region. Severe manifestations of desmoids were restricted to mutations between codons 1444 through 1581. Whereas 91% (75/82) of at-risk persons were excluded as mutation carriers, APC germline mutations were detected before clinical examination in 9% (7/82) of at-risk persons. One patient agreed to endoscopy only after mutation detection. ConclusionsThis study supports the feasibility of combined molecular and clinical screening of families with FAP and may provide a guideline for routine presymptomatic molecular diagnostics in a clinical laboratory.Familial adenomatous polyposis coli (FAP) is characterized by hundreds to thousands of colorectal adenomas that usually emerge during the second and third decade of life and harbor a high risk of malignant transformation. Patients Partly funded by a "Bundesministerium fur Bildung, Wissenschaft, For-schung und Technologie (BMBF)" grant #01-GB-9404.

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

“…APC mutations were compiled from Dobbie et al [1996], van der Luijt et al [1997], Armstrong et al [1997], Giarola et al [1999], Won et al [1999], Wallis et al [1999], Gebert et al [1999], Ponz de Leon et al [1999], Fidalgo et al [1999], Ficari et al [2000], Cao et al [2000], and Friedl et al [2001]. Major events, often overlooked in screenings [e.g., Wallis et al, 1999], are responsible for B10% of all cases of FAP [Su et al, 2000;Flintoff et al, 2001].…”

Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

“…It is possible that some individuals with APC mutation have a benign course and are probably never diagnosed due to the absence of any symptoms. Gebert with coworkers [24] reported one patient with a deletion at codon 1309, who was diagnosed at the age of 42, whereas one of his affected sons became symptomatic at the age of 7. Thus a sequence alteration at codon 1309 of exon 15 does not necessarily result in a phenotype with an early disease onset.…”

Hereditäres kolorektales Karzinom

“…Die genetische Diagnosesicherung durch einen Mutationsnachweis im APCGen auf dem langen Arm von Chromosom 5 (5q21-22) gelingt bei etwa 70-80% der Patienten [1,9]. Im Fall eines attenuierten kolonischen Phänotyps liegt die Rate des Mutationsnachweises dagegen nur bei 20-30% [1].…”