Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous.
OBJECTIVE
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.


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.


CONCLUSIONS
"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.
Renkonen
Elise T
ET
Department of Medical Genetics, Institute of Dentistry, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland.
Nieminen
Pekka
P
Abdel-Rahman
Wael M
WM
Moisio
Anu-Liisa
AL
Järvelä
Irma
I
Arte
Sirpa
S
Järvinen
Heikki J
HJ
Peltomäki
Päivi
P
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D005387:Finland; D017491:Genes, APC; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D012042:Registries