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MUTYH associated polyposis

Written2006-05Maartje Nielsen, Frederik J. Hes
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands

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Identity

Atlas_Id 10121
Genes implicated inMUTYH  
Inheritance MUTYH associated polyposis (MAP) is an autosomal recessive disorder, the frequency of heterozygotes carriers is 1-2% and the frequency of bi-allelic mutation carriers (according to Hardy-Weinberg equilibrium) lies between 1 per 10.000 and 40.000 newborns.

Clinics

Phenotype and clinics
  • The penetrance for colon polyps is close to 100% and bi-allelic MUTYH mutation carriers generally develop 10-100's adenomatous polyps/adenomas of the colon and the rectum.
  • Approximately one third of patients also develop polyps/adenomas in the upper gastrointestinal tract.
  • Other manifestations frequently seen in Familial Adenomatous Polyposis (FAP) are also present in minority of MAP patients: osteomas, pigmented retinal lesions (congenital hypertrophy of the retinal pigment epithelium; CHRPE) and tooth disorders. Recently also sebaceous gland tumors (Muir-Torre syndrome) and pilomatricomas have been reported in MAP-kindreds.
  • Neoplastic risk
  • Because of the development of multiple polyps, the risk for colorectal carcinoma is high. About 60-70% of MAP patients were diagnosed with colorectal carcinoma at a mean age of 47 years, most at first presentation. The actual penetrance is probably higher, because the development of colorectal carcinoma can be prevented through intensive colorectal screening.
  • Duodenum carcinoma reported in a minority (2 out of 50 MAP patients in the Netherlands).
  • Treatment
  • Colorectal screening, colonoscopy, starting from the age 20-25 years, every 2years.
  • Upper gastrointestinal tract screening from the age of 25-30 years, depending of the stage of identified tumours (Spigelman stadia), follow-up every 1-5 years.
  • In case the number of polyps is too large to be endoscopically removed, subtotal colectomy is indicated.
  • Prognosis When frequent colorectal and upper gastrointestinal tract screening is performed in a MAP-patient who has not developed (colorectal) carcinoma, the change of developing (colorectal) carcinoma is small and prognosis will be comparable to that of a healthy population.
    In MAP patients who have developed colorectal carcinoma, survival will depend on the age of diagnosis and (Dukes) stage of the colorectal carcinoma.

    Other findings

    Note In heterozygous MUTYH mutation carriers a (slight) increased risk for developing colorectal carcinoma has been found. A large case control research showed a relative risk of 1,5 for CRC in MUTYH heterozygous carriers aged > 55 years. Recently a ~3 fold increased risk in heterozygous carriers was found in a study based on relatives of MAP patients, which was significant in persons aged > 55 years and non-significant in persons aged < 55 years. So far, there is no conclusive evidence justifying colonoscopic screening in heterozygous MUTYH carriers.

    A possible relation between MUTYH and breast cancer has been reported because of a high prevalence of breast cancer cases in a group of Dutch female MAP patients (standardised morbidity ratio=3,75). Moreover, MUTYH knockout mouse that also carry heterozygous APC mutations are more prone to develop mammary tumours than APC-heterozygotes only. Case control studies will be necessary to confirm this relation in humans.

    In 148 gastric cancer cases one bi-allelic splice site mutation encoding a truncated MUTYH protein, c.IVS10-2A>G, was found. However, there was no significant higher number of MUTYH heterozygotes as compared to controls. Furthermore, no overrepresentation of MUTYH mutations (mono or bi-allelic) was found in patients with lung cancer, hepatocellular carcinoma, cholangiocarcinoma and (childhood) leukemia, compared to healthy controls.

    A suggested explanation for the relative absence of tumor growth at other places in MAP-patients is that oxidation is a more common effect in the digestive system and that the APC-gene has more sequences (AGAA or TGAA motifs, see heading somatic mutations) which are relatively dependent of MUTYH oxidative damage repair.

    Genes involved and Proteins

    Gene NameMUTYH (MUTYH (mutY homolog (E. coli)))
    Alias MYH hMYH MutY homolog MYHbeta
    Location 1p32.1-p34.3
    DNA/RNA
    Description The MUTYH gene is composed of 16 exons and 15 introns.
    Transcription The MUTYH gene encodes 11,4 kb, and the open reading frame consists of 1854 bp.
    Protein
     
      
    Description The full-length MUTYH protein contains 546 amino acids (60-65kDa). For mutation description the coding sequence is described and used, which differs because of the absence of 11 codons in exon 3.
    DESCRIPTION Alternative splicing generates a gene product of 521 amino Acids, referred as type 2. Type 1 is transported to the mitochondria, while type 2 lacks the first exon containing a mitochondrial targeting signal (MTS) and is transported to nucleus.
    Expression Expression of MUTYH has been found among others in the digestive system, germ cells, thymus,(rat-) brain, (mouse-) liver and (canine-) myocardium. Probably, the MUTYH protein is expressed widely, because the production of reactive oxygen species (ROS) leading to oxidative damage is generated during normal cellular oxygen metabolism and by oxygen stress conditions in all cells.
    Localisation MUTYH is located in the nucleus and mitochondria.
    Function The MUTYH protein is a base excision repair glycosylase which is involved in the repair of one of the most frequent and stable forms of oxidative damage, oxidation of a guanine leading to 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG). Other base excision repair glycosylases involved in oxidised guanine repair are the OGG1 and MTH1 protein (figure 1).

    MUTYH recognizes an oxoG:A mismatch and subsequently excises the undamaged adenine base using a base flipping mechanism. To a lesser extent also G:A, C:A, 8-oxoG:G and 8-oxoA:G mispairs are recognised and catalysed by MUTYH. The MUTYH protein consists of different functional domains. The N-terminal domain on the 5' side contains the catalytic region and includes a helix hairpin helix (HhH), pseudo HhH and an iron sulfur cluster loop motif, which are also common motifs in other BER glycosylases. The C-terminal domain on the 3' side is shares homology with MTH1 and plays a role in 8-oxoG recognition.
    Furthermore, MUTYH has binding sites for PCNA (proliferating cell nuclear antigen), RPA (replication protein A) and AP (apurinic/apyrimidinic) endonuclease. The interaction with these replication enzymes and a reported increase of expression during the S phase suggests a role for MUTYH especially in the replication-coupled repair. In E.coli it was demonstrated that the MUTYH homologue, mutY, recognizes the nascent strand in association with various cellular proteins such as PCNA or a mismatch repair genes complex. Remarkably, it was demonstrated that amino acid residues 232-254 of MUTYH interacts with the MSH2/MSH6 heterodimer via MSH6 and this interaction stimulates the glycosylase activities of MUTYH.

    Homology The percentage of similarity between the human muty gene (MUTYH) and that of various organisms is: 99% in chimpanzee, 80% in dog, 79% in mouse, 77% in rat, 66% in chicken and 41% in E.coli.
    Mutations
    Germinal About thirty pathogenic mutations in the MUTYH gene have been described; predominantly missense mutations, but to a lesser extent also small deletions, small insertions, (putative) splice site mutations and one gross deletion. Most common mutations found (in Western population) are the Tyr165Cys (Y165C) and Gly382Asp (G382D), which compromise about 70-75% of mutations in Western MAP patients.
    Other common mutations are: A371fs (c.1105delC, sometimes referred to as 1103delC); c.891+3A>C; P391L in Dutch patients (14%); Glu466del (c.1395delGGA) in Italian and the E466X in Indian people.
    The Y165C mutation is located in the pseudo HhH region that is involved in mismatch specificity and flipping of the adenine into the base specificity pocket. The G382D is located in the C-terminal domain involved in 8-oxoG recognition. In functional tests especially the Y165C, but also the G382D variants, have shown to be devoid of glycosylase activity directed towards 8-oxoG:A. The corresponding variant of G382D in mice, G365D, does not suppress the elevated spontaneous mutations in MUTHY-null ES cells and failed to prevent OGG1 from excising 8-oxo G opposite the generated AP site-which would then result in double strand DNA breaks.

    Recently, the 1105 delC variant showed significantly lowered binding and cleavage activities with heteroduplex oligonucleotides containing A:8-oxoG and 8-oxoA:G mispairs.
    Several SNP's (single nucleotide polymorphism) with amino acid substitutions have been registered in the NCBI database. Most frequently found in cases and controls: His 324Gln (Q324H) in 40-45% and IVS6+ 35 (462 +35) G>A in 20-25%. Pathogenic significance of the V22M SNP is disputed; it's prevalence in controls and in cases is comparable (10-15%).

    Somatic In the tumours of MAP patients specific G:C>T:A somatic transversions are found in APC and KRAS2 genes in up to 40% and 64% of cases, respectively. In APC G>T transversions have a predilection for G bases in AGAA or TGAA motifs, whereas in KRAS2 a preferential GGT>TGT transition of codon 12 (p.Gly12Cys) is found.

    All MAP tumours examined so far are MSI stable. One study found 18q LOH and P53 over-expression in the same frequency as in sporadic carcinomas. Few P53 mutations were found however and predominantly not G>T changes. No BRAF, SMAD4 or TGFBIIR mutations were detected in the same group of MAP-carcinomas. Twelve out of 13 MAP cancers tested were near-diploid. This last finding is in contrast with a more recent study that found aneuploidy in 80% of MAP-adenomas and also frequent losses at chromosome 1p, 17, 19, and 22 and gains affecting chromosomes 7 and 13. Authors explained the difference in outcomes because of the use of more sensitive and specific techniques in the last.


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    Citation

    This paper should be referenced as such :
    Nielsen, M ; Hes, F
    MUTYH associated polyposis
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):295-299.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/MYHpolypID10121.html


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