Abstract
BackgroundFamilial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations.MethodsFull genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations.Results10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC) both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA) developed colon cancer at age 72 as the first manifestation of attenuated FAP.ConclusionWith an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.
Highlights
Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features
The classical or intermediate phenotype is associated with mutations between codons 157 and 1595, whereas mutations before codon 157, in the alternatively spliced region of exon 9, and after codon 1595 cause attenuated FAP (AFAP) [8,9]
We present new APC mutations and discuss two cases that demonstrate the broad phenotypic spectrum in FAP; two sisters who concordantly developed classical polyposis, upper gastrointestinal polyps, and thyroid cancer and a woman with a 3'APC mutation who presented with the first symptom of FAP at age 72
Summary
Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations. Familial adenomatous polyposis (FAP) affects about 1/ 13–18000 individuals, is characterized by development of multiple colonic polyps and causes less than 1% of colorectal cancer [1,2]. A mutation cluster region in the 5'end of exon 15 of the APC gene has been identified and the two most frequent mutations, which account for 11–17% of the germline alterations, affect codons 1061 and 1309 [5]. The classical or intermediate phenotype is associated with mutations between codons 157 (in exon 4) and 1595 (in exon 15), whereas mutations before codon 157, in the alternatively spliced region of exon 9, and after codon 1595 cause attenuated FAP (AFAP) [8,9]
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