APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis

F. M. Giardiello, Gloria M Petersen, S. Piantadosi, S. B. Gruber, E. I. Traboulsi, G. J A Offerhaus, K. Muro, A. J. Krush, S. V. Booker, M. C. Luce, S. J. Laken, K. W. Kinzler, B. Vogelstein, S. R. Hamilton

Research output: Contribution to journalArticle

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Abstract

Background - Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome Sq. Aims - This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. Methods - Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. Results - FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. Conclusions-Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) ancipredisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

Original languageEnglish (US)
Pages (from-to)521-525
Number of pages5
JournalGut
Volume40
Issue number4
StatePublished - 1997
Externally publishedYes

Fingerprint

APC Genes
Adenomatous Polyposis Coli
Phenotype
Mutation
Codon
DNA Mismatch Repair
Pedigree
Cysts
Chromosomes
Neoplasms
Microsatellite Instability
Skin
Germ-Line Mutation
Genetic Association Studies
Genes

Keywords

  • APC gene mutation
  • Extraintestinal lesions
  • Familial adenomatous polyposis
  • Gardner syndrome
  • Phenotype

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Giardiello, F. M., Petersen, G. M., Piantadosi, S., Gruber, S. B., Traboulsi, E. I., Offerhaus, G. J. A., ... Hamilton, S. R. (1997). APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. Gut, 40(4), 521-525.

APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. / Giardiello, F. M.; Petersen, Gloria M; Piantadosi, S.; Gruber, S. B.; Traboulsi, E. I.; Offerhaus, G. J A; Muro, K.; Krush, A. J.; Booker, S. V.; Luce, M. C.; Laken, S. J.; Kinzler, K. W.; Vogelstein, B.; Hamilton, S. R.

In: Gut, Vol. 40, No. 4, 1997, p. 521-525.

Research output: Contribution to journalArticle

Giardiello, FM, Petersen, GM, Piantadosi, S, Gruber, SB, Traboulsi, EI, Offerhaus, GJA, Muro, K, Krush, AJ, Booker, SV, Luce, MC, Laken, SJ, Kinzler, KW, Vogelstein, B & Hamilton, SR 1997, 'APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis', Gut, vol. 40, no. 4, pp. 521-525.
Giardiello FM, Petersen GM, Piantadosi S, Gruber SB, Traboulsi EI, Offerhaus GJA et al. APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. Gut. 1997;40(4):521-525.
Giardiello, F. M. ; Petersen, Gloria M ; Piantadosi, S. ; Gruber, S. B. ; Traboulsi, E. I. ; Offerhaus, G. J A ; Muro, K. ; Krush, A. J. ; Booker, S. V. ; Luce, M. C. ; Laken, S. J. ; Kinzler, K. W. ; Vogelstein, B. ; Hamilton, S. R. / APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. In: Gut. 1997 ; Vol. 40, No. 4. pp. 521-525.
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abstract = "Background - Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome Sq. Aims - This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. Methods - Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. Results - FAP patients from the 42 families (82{\%}) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94{\%} and 92{\%} respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. Conclusions-Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) ancipredisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).",
keywords = "APC gene mutation, Extraintestinal lesions, Familial adenomatous polyposis, Gardner syndrome, Phenotype",
author = "Giardiello, {F. M.} and Petersen, {Gloria M} and S. Piantadosi and Gruber, {S. B.} and Traboulsi, {E. I.} and Offerhaus, {G. J A} and K. Muro and Krush, {A. J.} and Booker, {S. V.} and Luce, {M. C.} and Laken, {S. J.} and Kinzler, {K. W.} and B. Vogelstein and Hamilton, {S. R.}",
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T1 - APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis

AU - Giardiello, F. M.

AU - Petersen, Gloria M

AU - Piantadosi, S.

AU - Gruber, S. B.

AU - Traboulsi, E. I.

AU - Offerhaus, G. J A

AU - Muro, K.

AU - Krush, A. J.

AU - Booker, S. V.

AU - Luce, M. C.

AU - Laken, S. J.

AU - Kinzler, K. W.

AU - Vogelstein, B.

AU - Hamilton, S. R.

PY - 1997

Y1 - 1997

N2 - Background - Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome Sq. Aims - This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. Methods - Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. Results - FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. Conclusions-Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) ancipredisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

AB - Background - Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome Sq. Aims - This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. Methods - Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. Results - FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. Conclusions-Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) ancipredisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

KW - APC gene mutation

KW - Extraintestinal lesions

KW - Familial adenomatous polyposis

KW - Gardner syndrome

KW - Phenotype

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