Alterations of the base excision repair gene MUTYH in sporadic colorectal cancer

Abstract

The base excision repair gene MUTYH encodes glycosylase which removes adenine residues mispaired with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHG). Biallelic germline mutations of the MUTYH gene are known to cause multiple colorectal adenomas including polyposis and cancer, mostly due to G:C➝T:A transversions in proto-oncogenes or tumor suppressor genes. The risk of colorectal cancer (CRC) in monoallelic mutation carriers of MUTYH is estimated to be higher in comparison with non-carriers. To investigate the possible role in sporadic CRC, we examined alterations of the MUTYH gene including somatic mutations and allelic loss in 101 cases of sporadic CRC, together with the KRAS mutation in some cases. MUTYH mutations in cancer DNA were detected in 3 cases, while mutations were also found in DNA samples from normal tissues, indicating that all were germline mutations. Allelic loss at the MUTYH locus was found in 10 of 51 (20.0%) CRC cases and KRAS mutations were found in 33 of the 101 (32.7%) samples. There was no significant difference in the rate of G:C➝T:A transversion in KRAS between cases with allelic loss (1 of 10, 10.0%) and without allelic loss (9 of 41, 22.0%). Investigation of quantitative allelic imbalance at SNP rs3219489 of MUTYH showed that CRC cases with C allele dominance (minor type corresponding to His) were more frequently detected with G:C➝T:A transversions than in those with G allele dominance (major type corresponding to Gln). In conclusion, somatic alterations of MUTYH in sporadic CRC were rare, similar to other DNA repair genes. However, it is possible that unknown mutations of regions not analyzed in this study and epigenetic changes of the promoter region of MUTYH may contribute to the disease.

Impaired 8-Hydroxyguanine Repair Activity of MUTYH Variant p.Arg109Trp Found in a Japanese Patient with Early-Onset Colorectal Cancer

“…Since neither the p.Arg19* nor the p.Arg109Trp variation was observed in our screening of 100 Japanese control individuals, these variants are considered to be relatively rare among the general Japanese population. In addition to the fact that the two major pathogenic MUTYH mutations of p.Tyr179Cys and p.Gly396Asp have not been seen in Japanese individuals in previous studies [13–15] or the present study, the p.Arg19* and p.Arg109Trp variations as well as the p.Gly286Glu variation, rather than the p.Tyr179Cys and p.Gly396Asp variations, are thought to account for functionally impaired MUTYH alleles in the Japanese population. A combination of these MUTYH variations would cause an even higher susceptibility to MAP.…”

“…The p.Gly286Glu mutation was found as a homozygous mutation in a Japanese patient with colorectal multiple polyps and a carcinoma by Yanaru-Fujisawa et al [14], and in the paper, mouse MUTYH mutant protein corresponding to the human p.Gly286Glu was shown to have an impaired repair activity. However, this mutation has not been detected in other MUTYH mutation screenings performed in Japanese CRC patients [13–15], including the current study, and whether the p.Gly286Glu pathogenic mutation is common in the Japanese population remains unclear. The p.Arg19* detected in our analysis was previously found as a heterozygous mutation in one Japanese patient with CRC reported by Kuno et al [15], suggesting that it could be relatively common impaired MUTYH mutation in the Japanese population.…”

“…However, this mutation has not been detected in other MUTYH mutation screenings performed in Japanese CRC patients [13–15], including the current study, and whether the p.Gly286Glu pathogenic mutation is common in the Japanese population remains unclear. The p.Arg19* detected in our analysis was previously found as a heterozygous mutation in one Japanese patient with CRC reported by Kuno et al [15], suggesting that it could be relatively common impaired MUTYH mutation in the Japanese population. On the other hand, the p.Arg109Trp also detected in our analysis is the first demonstration of such a variant in the Japanese population.…”

“…Various pathogenic MUTYH mutations, including two major mutations (p.Tyr179Cys and p.Gly396Asp), have been detected in MAP patients in several ethnic populations [12]; however, neither the p.Tyr179Cys nor the p.Gly396Asp mutation has been found in the Japanese population [13–15], and which MUTYH variations are the major pathogenic mutations in the Japanese population remains unclear. In accordance with the notion that early-onset cancer is likely to be associated with the germline abnormality of certain gene(s) [16], early-onset colorectal cancer (CRC) is one of the characteristics of MAP [12], and early-onset CRC is thought to occur in patients with biallelic-inactivating mutations of another 8OHG repair gene, OGG1 .…”

Variants of Base Excision Repair Genes <b><i>MUTYH</i></b>, <b><i>PARP1</i></b> and <b><i>XRCC1</i></b> in Alzheimer's Disease Risk

“…The only available data are on an increased risk of lung and colorectal cancers and end-stage renal disease in patients with the c.972G>C polymorphism in an Asian population [58,59,60]. The relationship between the MUTYH gene polymorphism and age-related macular degeneration (AMD) has also been examined.…”