Adenomatous Polyposis Families That Screen APC Mutation–Negative by Conventional Methods Are Genetically Heterogeneous Elise T. Renkonen, Pekka Nieminen, Wael M. Abdel-Rahman, Anu-Liisa Moisio, Irma Ja ¨rvela ¨, Sirpa Arte, Heikki J. Ja ¨rvinen, and Pa ¨ivi Peltoma ¨ki A B S T R A C T 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 expres- sion 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. J Clin Oncol 23:5651-5659. © 2005 by American Society of Clinical Oncology INTRODUCTION Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome character- ized by the development by age 20 years of multiple colorectal polyps; one or several of these polyps progresses to cancer by approx- imately 40 years of age. 1 In classical FAP, at least 100 (often hundreds to more than a thousand) adenomas are present, whereas polyposis with fewer than 100 adenomas per patient is referred to as attenuated polyposis (AFAP or AAPC). In addition to colorectal polyps, affected individuals may develop various extracolonic manifestations, such as desmoid tumors, duodenal adenomas, mandibular osteomas, and hypertrophic pigmentary lesions of the retina. In AFAP, the age at onset of adenomas and cancer is higher, and the lifetime risk of cancer is lower compared with classical FAP. 2 While the true incidence and frequency of AFAP is 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. Submitted February 3, 2005; accepted April 19, 2005. 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 Devel- opment Funds (EVO), and Helsinki Biomedical Graduate School. Authors’ disclosures of potential con- flicts of interest are found at the end of this article. Address reprint requests to Pa ¨ ivi Peltoma ¨ ki, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland; e-mail: paivi.peltomaki@helsinki.fi. © 2005 by American Society of Clinical Oncology 0732-183X/05/2324-5651/$20.00 DOI: 10.1200/JCO.2005.14.712 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 23  NUMBER 24  AUGUST 20 2005 5651 Downloaded from jco.ascopubs.org on April 5, 2016. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.