Abstract

Background: The patient with ten or more adenomas in the colon poses a diagnostic challenge. Beside germline mutations in the APC and MUTYH genes, only four cases of mosaic APC mutations have been reported.

Aim: Given the relatively high frequency of de novo APC mutations in familial adenomatous polyposis (FAP), we investigated whether the proportion of somatic mosaic APC mutations is currently underestimated.

Methods: Between January 1, 1994 and 31 December, 2005 we performed germline mutation analysis in 599 consecutive index-patients with polyposis coli referred for diagnostic APC scanning using a combination of denaturing gradient gel electrophoresis (DGGE) and, protein truncation test (PTT). Variants were analyzed by direct sequencing with primers flanking those used for DGGE and PTT, and quantified using pyrosequencing.

Results: Scrutinizing the molecular genetic results and family data of 242 index-patients with pathogenic APC mutations lead to the identification of ten mosaic cases (4%). We observed C>T transitions in CGA-sites in four of the ten cases with somatic mosaicism, which is significantly more than 26 of the 232 non-mosaic cases (p=0.02). Phenotypes of patients with somatic mosaicism ranged from an attenuated form of polyposis coli to florid polyposis with major extra-colonic manifestations.

Conclusions: Mosaicism occurs in a significant number of APC mutations and we estimate that one fifth of the de novo cases of FAP are mosaic. Clinically, the severity of manifestations in offspring and the recurrence risk for siblings of apparently sporadic polyposis patients may be underestimated due to parental APC mosaicism.