Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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.
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.
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 SNPs (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; its prevalence in controls and in cases is comparable (10-15%).
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.