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Adenomatous Polyposis Families That Screen APC Mutation–Negative by Conventional Methods Are Genetically Heterogeneous

From the Department of Medical Genetics, Institute of Dentistry, and Institute of Biotechnology, University of Helsinki; Laboratory of Molecular Genetics, Department of Oral and Maxillofacial Diseases, and Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland

Address reprint requests to Päivi Peltomäki, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland; e-mail: paivi.peltomaki{at}helsinki.fi

PURPOSE: One third of families with classical adenomatous polyposis (FAP), and a majority of those with attenuated FAP (AFAP), remain APC mutation–negative by conventional methods. Our purpose was to clarify the genetic basis of polyposis and genotype-phenotype correlations in such families.

PATIENTS AND METHODS: We studied a cohort of 29 adenomatous polyposis families that had screened APC mutation–negative by the protein truncation test, heteroduplex analysis, and exon-specific sequencing. The APC gene was investigated for large genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA), and for allelic mRNA expression by single nucleotide primer extension (SNuPE). The AXIN2 gene was screened for mutations by sequencing.

RESULTS: Four families (14%) showed a constitutional deletion of the entire APC gene (three families) or a single exon (one family). Seven families (24%) revealed reduced or extinct mRNA expression from one APC allele in blood, accompanied by loss of heterozygosity in the APC region in six (75%) of eight tumors. In 15 families (52%), possible APC involvement could be neither confirmed nor excluded. Finally, as detailed elsewhere, three families (10%) had germline mutations in genes other than APC, AXIN2 in one family, and MYH in two families.

CONCLUSION: "APC mutation–negative" FAP is genetically heterogeneous, and a combination of MLPA and SNuPE is able to link a considerable proportion (38%) to APC. Significant differences were observed in clinical manifestations between subgroups, emphasizing the importance of accurate genetic and clinical characterization for the proper management of such families.

Supported by grants from the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Cancer Foundation, K. Albin Johansson Foundation, Helsinki University Hospital Research and Development Funds (EVO), and Helsinki Biomedical Graduate School.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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