Mutational spectrum of the APC and MUTYH genes and genotype–phenotype correlations in Brazilian FAP, AFAP, and MAP patients
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Published:2013-04-05
Issue:1
Volume:8
Page:
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ISSN:1750-1172
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Container-title:Orphanet Journal of Rare Diseases
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language:en
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Short-container-title:Orphanet J Rare Dis
Author:
Torrezan Giovana Tardin,da Silva Felipe Cavalcanti Carneiro,Santos Érika Maria Monteiro,Krepischi Ana Cristina Victorino,Achatz Maria Isabel Waddington,Junior Samuel Aguiar,Rossi Benedito Mauro,Carraro Dirce Maria
Abstract
Abstract
Background
Patients with multiple colorectal adenomas are currently screened for germline mutations in two genes, APC and MUTYH. APC-mutated patients present classic or attenuated familial adenomatous polyposis (FAP/AFAP), while patients carrying biallelic MUTYH mutations exhibit MUTYH-associated polyposis (MAP). The spectrum of mutations as well as the genotype-phenotype correlations in polyposis syndromes present clinical impact and can be population specific, making important to obtain genetic and clinical data from different populations.
Methods
DNA sequencing of the complete coding region of the APC and MUTYH genes was performed in 23 unrelated Brazilian polyposis patients. In addition, mutation-negative patients were screened for large genomic rearrangements by multiplex ligation-dependent probe amplification, array-comparative genomic hybridization, and duplex quantitative PCR. Biallelic MUTYH mutations were confirmed by allele-specific PCR. Clinical data of the index cases and their affected relatives were used to assess genotype–phenotype correlations.
Results
Pathogenic mutations were identified in 20 of the 23 probands (87%): 14 in the APC gene and six in the MUTYH gene; six of them (30%) were described for the first time in this series. Genotype-phenotype correlations revealed divergent results compared with those described in other studies, particularly regarding the extent of polyposis and the occurrence of desmoid tumors in families with mutations before codon 1444 (6/8 families with desmoid).
Conclusions
This first comprehensive investigation of the APC and MUTYH mutation spectrum in Brazilian polyposis patients showed a high detection rate and identified novel pathogenic mutations. Notably, a significant number of APC-positive families were not consistent with the predicted genotype-phenotype correlations from other populations.
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Genetics (clinical),General Medicine
Reference55 articles.
1. Gardner EJ, Burt RW, Freston JW: Gastrointestinal Polyposis: Syndromes and Genetic Mechanisms. West J Med. 1980, 132: 488-499. 2. Leppert M, Dobbs M, Scambler P, O'Connell P, Nakamura Y, Stauffer D, Woodward S, Burt R, Hughes J, Gardner E: The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987, 238: 1411-1413. 10.1126/science.3479843. 3. Knudsen AL, Bisgaard ML, Bülow S:Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003, 2: 43-55. 10.1023/A:1023286520725. 4. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP: Inherited variants of MYH associated with somatic G:C > T:A mutations in colorectal tumors. Nat Genet. 2002, 30: 227-232. 10.1038/ng828. 5. Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, Finniea R, Matrkam A, Groffen J, Boguski MS, Altschul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y: Identification of FAP locus genes from chromosome 5q21. Science. 1991, 253: 661-665. 10.1126/science.1651562.
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