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Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous.
J Clin Oncol. 2005 Aug 20; 23(24):5651-9.JC

Abstract

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.

Authors+Show Affiliations

Department of Medical Genetics, Institute of Dentistry, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16110024

Citation

Renkonen, Elise T., et al. "Adenomatous Polyposis Families That Screen APC Mutation-negative By Conventional Methods Are Genetically Heterogeneous." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 23, no. 24, 2005, pp. 5651-9.
Renkonen ET, Nieminen P, Abdel-Rahman WM, et al. Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous. J Clin Oncol. 2005;23(24):5651-9.
Renkonen, E. T., Nieminen, P., Abdel-Rahman, W. M., Moisio, A. L., Järvelä, I., Arte, S., Järvinen, H. J., & Peltomäki, P. (2005). Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 23(24), 5651-9.
Renkonen ET, et al. Adenomatous Polyposis Families That Screen APC Mutation-negative By Conventional Methods Are Genetically Heterogeneous. J Clin Oncol. 2005 Aug 20;23(24):5651-9. PubMed PMID: 16110024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous. AU - Renkonen,Elise T, AU - Nieminen,Pekka, AU - Abdel-Rahman,Wael M, AU - Moisio,Anu-Liisa, AU - Järvelä,Irma, AU - Arte,Sirpa, AU - Järvinen,Heikki J, AU - Peltomäki,Päivi, PY - 2005/8/20/pubmed PY - 2005/9/24/medline PY - 2005/8/20/entrez SP - 5651 EP - 9 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 23 IS - 24 N2 - 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. SN - 0732-183X UR - https://www.unboundmedicine.com/medline/citation/16110024/Adenomatous_polyposis_families_that_screen_APC_mutation_negative_by_conventional_methods_are_genetically_heterogeneous_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2005.14.712?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -