Article

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype

Institute of Human Genetics, University of Bonn, Bonn, Germany.
International Journal of Cancer (Impact Factor: 5.01). 08/2006; 119(4):807-14. DOI: 10.1002/ijc.21905
Source: PubMed

ABSTRACT To determine the frequency, mutation spectrum and phenotype of the recently described autosomal recessive MUTYH-associated polyposis (MAP), we performed a systematic search for MUTYH (MYH) mutations by sequencing the complete coding region of the gene in 329 unselected APC mutation-negative index patients with the clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP). Biallelic germline mutations in MUTYH were identified in 55 of the 329 unselected patients (17%) and in another 9 selected index cases. About one-fifth (20%) of the 64 unrelated MAP patients harboured none of the 2 hot-spot missense mutations Y165C and/or G382D. Including 7 affected relatives, almost all MAP patients presented with either an attenuated (80%) or with an atypical phenotype (18%). Fifty percentage of the MAP patients had colorectal cancer at diagnosis. Duodenal polyposis was found in 18%, thyroid and stomach cancer in 1 case, other extraintestinal manifestations associated with FAP were not observed. In 8 families, vertical segregation was suspected; in 2 of these families, biallelic mutations were identified in 2 generations. Monoallelic changes with predicted functional relevance were found in 0.9% of the 329 patients, which is in accordance with the carrier frequency in the general population. In conclusion, biallelic MUTYH mutations are the underlying genetic basis in a substantial fraction of patients with adenomatous polyposis. The phenotype of MAP is best characterised as attenuated or atypical, respectively. Colorectal surveillance starting at about 18 years of age is recommended for biallelic mutation carriers and siblings of MAP patients, who refuse predictive testing.

1 Follower
 · 
96 Views
  • Source
    Zeitschrift für Gastroenterologie 08/2013; 51(8):753-854. DOI:10.1055/s-0033-1350264 · 1.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There have been recent advances in genetic testing enabling accurate diagnosis of polyposis syndromes by identifying causative gene mutations, which is essential in management of individuals with polyposis syndrome and predictive genetic testing of their extended families. There are some similarities in clinical presentation of various polyposis syndromes, which may pose challenge to diagnosis. In this review, we will discuss the clinical presentation of the main polyposis syndromes and the process of genetic testing, including the latest advancement and future of genetic testing. We aim to reiterate the importance of genetic testing in management of polyposis syndromes, potential pitfalls associated with genetic testing and recommendations for health care professionals involved with care of polyposis patients. This article is protected by copyright. All rights reserved.
    Colorectal Disease 02/2014; 16(8). DOI:10.1111/codi.12600 · 2.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 15-25% of breast cancers are identified in women with a family history of breast cancer. Yet, germline mutations in the currently known breast cancer susceptibility genes account for only one-third of familial breast cancer cases. In 2002, our research group had identified the CHEK2 1100delC mutation as a breast cancer susceptibility allele. It was estimated that this mutation confers an approximately 2-fold increased breast cancer risk for female CHEK2 1100delC carriers. Although this 2-fold increased breast cancer risk had classified the CHEK2 1100delC mutation as a moderate-risk breast cancer susceptibility allele, the mutation typically was more prevalent among breast cancer families with a high-risk breast cancer inheritance pattern. Also, the CHEK2 1100delC mutation did not completely segregate with the breast cancer phenotype in the high-risk breast cancer families. Together, these observations suggested the presence of additional cance! r susceptibility alleles in CHEK2 1100delC families. This thesis has focused on three topics related to the CHEK2 gene and in particular the CHEK2 1100delC mutation: analysis of the CHEK2-p53 tumor suppressor pathway by mutation analysis of both genes in human breast cancer cell lines; evaluation of the association of CHEK2 1100delC with male breast cancer and colorectal cancer; and identification of genes involved in the polygenic CHEK2 cancer model by using a candidate gene approach.

Preview

Download
0 Downloads