MUTYH associated polyposis (MAP)

Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
Current Genomics (Impact Factor: 2.34). 09/2008; 9(6):420-35. DOI: 10.2174/138920208785699562
Source: PubMed


MUTYH Associated Polyposis (MAP), a Polyposis predisposition caused by biallelic mutations in the Base Excision Repair (BER) gene MUTYH, confers a marked risk of colorectal cancer (CRC). The MAP phenotype is difficult to distinguish from other hereditary CRC syndromes. Especially from Familial Adenomatous Polyposis (FAP) and to a lesser extend Lynch Syndrome, which are caused by germline mutations in the APC and Mismatch Repair (MMR) genes, respectively.
Here we review research findings regarding MUTYH interactions, genotypic and phenotypic characteristics of MAP, as well as surveillance and treatment of the disease. The applied papers, published between 1/1 2002- 1/2 2008, were found through PubMed.
The exact role of MUTYH in CRC tumorgenesis is still uncertain, although MAP tumors show distinct molecular features, including somatic G:C>T:A transversions in the APC gene. Furthermore, cooperation between the BER and the MMR systems exists, as MUTYH interacts with MMR gene-products. Possibly, monoallelic defects in both pathways are of significance to CRC development.
Specific MUTYH variants are found to be characteristic in distinct ethnic populations, which could facilitate future genetic screening. Knowledge concerning functional consequences of many MUTYH germline mutations remains sparse. Most thoroughly investigated are the two most common MUTYH variants, Y179C and G396D, both generating dysfunctional gene products.
Phenotypic features of MAP include: development of 10-100 colorectal adenomas, debuting at 46-47 years, often CRC at time of clinical diagnosis, and in some, development of extracolonic manifestations.

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Available from: Marie Louise Mølgaard Binderup, Sep 17, 2014
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    • "Other manifestations such as osteomas, dental cysts and congenital hypertrophy of the retinal pigment epithelium (CHRPE) are also seen in this group of patients (32, 71, 72). These extra colonic manifestations are also reported in FAP patients and the occurrence is less in MAP than in FAP or AFAP patients (73). The association between breast cancer and MUTYH gene is not defined clearly so far (71). "
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    ABSTRACT: Colorectal cancer is classified in to three forms: sporadic (70-75%), familial (20-25%) and hereditary (5-10%). hereditary colorectal cancer syndromes classified into two different subtypes: polyposis and non polyposis. Familial Adenomatous polyposis (FAP; OMIM #175100) is the most common polyposis syndrome, account for <1% of colorectal cancer incidence and characterized by germline mutations in the Adenomatous polyposis coli (APC, 5q21- q22; OMIM #175100). FAP is a dominant cancer predisposing syndrome which 20-25% cases are de novo. There is also another polyposis syndrome; MUTYH associated polyposis (MAP, OMIM 608456) which it is caused by mutation in human Mut Y homologue MUTYH (MUTYH; OMIM 604933) and it is associated with multiple (15-100) colonic adenomas. In this paper we discuss MUTYH mechanism as an important member of Base Excision Repair (BER) family and its important role in polyposis condition.
    Full-text · Article · Mar 2013 · Gastroenterology and hepatology from bed to bench
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    • "A number of variants appear recurrent in different populations, with Y179C (previously annotated as Y165C) and G396D (previously annotated as G382D) missense mutations accounting together for about 70% of germline alterations found in European patients (reviewed by Cheadle and Sampson, 2007); however, in Asian populations, Y179C and G396D must be rare, since neither mutation has been found in MAP patients. On the other hand, other mutations have proven to be recurrent in patients from particular populations (reviewed by Poulsen and Bisgaard, 2008). Taken together, these findings indicate that sequencing of the entire MUTYH open reading frame has to be performed for the genetic testing, especially in populations of mixed ethnicity. "
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    ABSTRACT: In 2002, Al-Tassan and co-workers described for the first time a recessive form of inherited polyposis associated with germline mutations of MUTYH, a gene encoding a base excision repair (BER) protein that counteracts the DNA damage induced by the oxidative stress. MUTYH-associated polyposis (MAP) is now a well-defined cancer susceptibility syndrome, showing peculiar molecular features that characterize disease progression. However, some aspects of MAP, including diagnostic criteria, genotype-phenotype correlations, pathogenicity of variants, as well as relationships between BER and other DNA repair pathways, are still poorly understood. A deeper knowledge of the MUTYH expression pattern is likely to refine our understanding of the protein role and, finally, to improve guidances for identifying and handling MAP patients.
    Full-text · Article · Aug 2012 · Frontiers in Oncology
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    • "Although the majority of MUTYH mutations present in Caucasian MAP patients are located in exons 7 and 13, several additional pathogenic variants are scattered over all other exons of the gene in the Caucasian population [35]. In addition, the distribution of MUTYH mutations differs among populations [36]. Therefore, in order to allow maximum sensitivity, mutation scanning needs to be performed on all MUTYH exons. "
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    ABSTRACT: MUTYH-associated polyposis (MAP) is an autosomal recessive form of intestinal polyposis predisposing to colorectal carcinoma. High resolution melting analysis (HRMA) is a mutation scanning method that allows detection of heterozygous sequence changes with high sensitivity, whereas homozygosity for a nucleotide change may not lead to significant curve shape or melting temperature changes compared to homozygous wild-type samples. Therefore, HRMA has been mainly applied to the detection of mutations associated with autosomal dominant or X-linked disorders, while applications to autosomal recessive conditions are less common. MUTYH coding sequence and UTRs were analyzed by both HRMA and sequencing on 88 leukocyte genomic DNA samples. Twenty-six samples were also examined by SSCP. Experiments were performed both with and without mixing the test samples with wild-type DNA. The results show that all MUTYH sequence variations, including G > C and A > T homozygous changes, can be reliably identified by HRMA when a condition of artificial heterozygosity is created by mixing test and reference DNA. HRMA had a sensitivity comparable to sequencing and higher than SSCP. The availability of a rapid and inexpensive method for the identification of MUTYH sequence variants is relevant for the diagnosis of colorectal cancer susceptibility, since the MAP phenotype is highly variable.
    Full-text · Article · Jul 2011 · BMC Cancer
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