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Aretz S, Uhlhaas S, Goergens H, et al.. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with attenuated or atypical phenotype. Int J Cancer. 119: 807-814

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.

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    • "cancer (HNPCC), recent studies have identified a new gene implicated in hereditary CRC, the human homologue of the base excision repair (BER) gene MutY (MYH), which encodes a member of the base excision repair system and has been involved in the occurrence of MYH associated polyposis (MAP) that is a new adenoma-prone phenotype (Al-Tassan et al., 2002; Dickson et al., 2008; Aretz et al., 2006; Nielsen et al., 2011). MYH is a DNA glycosylase that acts at a third level of defense, in charge for removing the mispaired 8-OG, one of the most mutagenic DNA products of oxidative DNA damage, form DNA of adenines (Slupska et al., 1996; 6404 Hayashi et al., 2002). "
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    ABSTRACT: Purpose: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associated with colorectal neoplasms that display somatic G:C?T:A transversions. However, the effect of single germline variants has not been widely studied, prompting the present investigation of monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC) in a Chinese population. Patients and Methods: Between January 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donors were screened randomly for 7 potentially pathogenic germline MYH exons using genetic testing technology. Variants of heterozygosity at the MYH locus were assessed in both sporadic cancer patients and healthy controls. Univariate and multivariate analyses were performed to determine risk factors for cancer onset. Results: Five monoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which were detected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1 proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 G?A, exon 1-292 G?A and intron 1+11 C?T, being identified in 13 CRC patients and 2 normal blood donors. A variant of base replacement, intron 10-2 A?G, was identified in the exon 10 region in 21 cases and 7 controls, while a similar type of variant in the exon 13 region, intron 13+12 C?T, was identified in 8 cases and 6 controls. Not the only but a newly missense variant in the present study, p. V463E (Exon 14+74 T?A), was identified in exon 14 in 6 patients and 1 normal control. In exon 16, nt. 1678-80 del GTT with loss of heterozygosity (LOH) was identified in 27 CRC cases and 26 controls. There was no Y165C in exon 7 or G382D in exon 14, the hot- spot variants which have been reported most frequently in Caucasian studies. After univariate analysis and multivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 A?G (p=0.004) and p. V463E (p=0.036) in the MYH gene were selected as 3 independent risk factors for CRC. Conclusions: According to these results, the linked variant in Exon 1 region, Intron 10-2 A?G of base replacement and p. V463E of missense variant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility to sporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic difference in MYH gene.
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