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Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation

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Diseases of the Colon & Rectum

Abstract

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In the present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of desmoid neoplasms) associated with an unusual mutation of the adenomatosis polyposis coli gene. If confirmed by other investigations, these findings might help to understand the biologic mechanisms by which specific adenomatosis polyposis coli mutations predispose to desmoid tumors. METHODS: The family with familial adenomatous polyposis, living in southern Italy, was studied from 1985 to the end of 1999; at this date, 15 individuals have been affected by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors. A total of 19 family members were studied for adenomatosis polyposis coli gene mutations; 13 of them tested positive and 6 negative. The analytical procedure—previously described—consisted of the extraction of peripheral blood cell DNA, amplification of exon 15 by polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing of the DNA fragment containing the mutation. RESULTS: The main clinical features of the family were 1) a high frequency of desmoid tumors and, consequently, a high penetrance of the desmoid trait in all branches of the family and in 11 (73.3 percent) of 15 affected individuals and 2) severity of desmoids in at least 4 family members, 2 of whom died for causes related to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting of a large deletion of 310 base pairs at codon 1,464, with duplication of the breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the adenomatosis polyposis coli gene at the beginning of the region frequently associated with desmoids induced a familial adenomatous polyposis phenotype featured by a high penetrance of the desmoid trait, with severe disease in several affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli.

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Authors and Affiliations

  1. From the Dipartimento di Medicina Interna, Università di Modena, Modena, Italy

    Maurizio Ponz de Leon M.D., Piero Benatti M.D., Antonio Percesepe M.D. & Luca Roncucci M.D.

  2. Laboratorio di Oncologia Sperimentale, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

    Liliana Varesco M.D. & Viviana Gismondi Ph.D.

  3. Divisione di Endoscopia Digestiva, Ospedale di Reggio Emilia, Reggio Emilia, Italy

    Romano Sassatelli M.D.

  4. Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli, Naples, Italy

    Paola Izzo Ph.D., Maria Irene Scarano Ph.D. & Marina de Rosa M.D.

  5. Servizio di Endoscopia, Istituto dei Tumori “Pascale”, Naples, Italy

    Giovanni Battista Rossi M.D.

  6. Divisione di Anatomia Patologica, Ospedale di Carpi (Mo), Carpi, Italy

    Carmela Di Gregorio M.D.

Authors
  1. Maurizio Ponz de Leon M.D.
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  2. Liliana Varesco M.D.
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  3. Piero Benatti M.D.
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  4. Romano Sassatelli M.D.
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  5. Paola Izzo Ph.D.
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  6. Maria Irene Scarano Ph.D.
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  7. Giovanni Battista Rossi M.D.
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  8. Carmela Di Gregorio M.D.
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  9. Viviana Gismondi Ph.D.
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  10. Antonio Percesepe M.D.
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  11. Marina de Rosa M.D.
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  12. Luca Roncucci M.D.
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Additional information

Supported, in part, by grants from the Italian Ministry of the Education and University (funds 60 and 40 percent), the Consiglio Nazionale delle Ricerche (CNR project “Applicazioni Cliniche della Ricerca Oncologica”), the Associazione Italiana per la Ricerca sul Cancro (special project “Hereditary Colorectal Cancer,” 1994–1997 and funds of 1998), and the Region Emilia-Romagna (legge 1970, 15.3.1986).

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de Leon, M.P., Varesco, L., Benatti, P. et al. Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation. Dis Colon Rectum 44, 1597–1604 (2001). https://doi.org/10.1007/BF02234378

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  • DOI: https://doi.org/10.1007/BF02234378

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