Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas

Isidro, Glória; Laranjeira, Francisco; Pires, Ana Sofia; Leite, Júlio Soares; Regateiro, Fernando; Sousa, F. Castro e; Soares, José; Castro, Clara; Gíria, João; Brito, María José; Medeira, Ana; Teixeira, Ricardo; Morna, Henrique; Gaspar, Isabel; Marinho, Carla; Jorge, Rosa; Brehm, António; Ramos, José Silva; Boavida, Maria Guida

doi:10.1002/humu.9282

Cited by 90 publications

(72 citation statements)

References 22 publications

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“…The frequencies of the previously reported MUTYH polymorphisms were consistent with published data. 9,11,12 The inclusion criteria, results of the tumour tissue examination and mutation analysis are summarised in Table 1.…”

Section: Resultsmentioning

confidence: 99%

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No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

et al. 2008

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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumour predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. In contrast to MLH1 and MSH2, germline mutations in MSH6 are associated with a milder and particularly variable phenotype. Based on the reported interaction of the MMR complex and the base excision repair protein MUTYH, it was hypothesised that MUTYH mutations serve as phenotypical modifiers in HNPCC families. Recently, a significantly higher frequency of heterozygosity for MUTYH mutations among MSH6 mutation carriers was reported. We examined 64 MSH6 mutation carriers (42 truncating mutations, 19 missense mutations and 3 silent mutations) of the German HNPCC Consortium for MUTYH mutations by sequencing the whole coding region of the gene. Monoallelic MUTYH mutations were identified in 2 of the 64 patients (3.1%), no biallelic MUTYH mutation carrier was found. The frequency of MUTYH mutations was not significantly higher than that in healthy controls, neither in the whole patient group (P ¼ 0.30) nor in different subgroups regarding mutation type. Our results do not support the association between MSH6 mutations and heterozygosity for MUTYH mutations.

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Section: Resultsmentioning

confidence: 99%

“…11 She had been diagnosed with an MSS rectal cancer at the age of 51 years, and her family history met the Amsterdam criteria. Her tumour tissue was positive for all tested MMR proteins in immunohistochemical staining.…”

Section: Resultsmentioning

confidence: 99%

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

et al. 2008

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“…In previous studies, MYH-associated tumors have shown a high frequency of G>T mutations in APC and KRAS, in accordance with defective BER (Al-Tassan, et al, 2002;Jones, et al, 2004;. Approximately 85% of Caucasian patients with MYH mutations carry the (c.494A>G) p.Y165C or (c.1145G>A) p.G382D variants, and only about twelve other likely pathogenic variants [(c.970C>T) Fleischmann, et al, 2004;Gismondi, et al, 2004;Isidro, et al, 2004;. However, specific variants have been identified in different ethnic populations, including (c.1396G>T) p.E466X in the Indian and (c.270C>A) p.Y90X in the Pakistani population .…”

Section: Introductionmentioning

confidence: 82%

A novel functionally deficientMYH variant in individuals with colorectal adenomatous polyposis

et al. 2005

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Inherited biallelic mutations in the base excision repair gene MYH confer susceptibility to colorectal adenomas and carcinoma. Approximately 85% of Caucasians with MYH mutations carry the (c.494A>G) p.Y165C and (c.1145G>A) p.G382D variants. Only a few other clearly pathogenic mutations have been identified, and mutation analyses tend to focus on the two founder mutations rather than the whole coding region of the gene. We sequenced the entire coding region of MYH in a population-based series of 24 Finnish APCmutation negative polyposis patients in order to identify novel pathogenic MYH variants. A population-based series of 1,042 Finnish colorectal cancer patients and 85 cancer-free controls were available for further evaluation. A functional cleavage assay was designed to evaluate consequences of possible novel variants to protein function. Three novel MYH variants, (c.270C>T) p.Y90Y, (c.1376C>A) p.A459D, and (c.1389G>C) p.T469T, were observed. p.A459D variant in exon 14 was identified in two patients from the polyposis series, once in homozygosity and once in compound heterozygosity with p.Y165C. In the population-based series of 1,042 colorectal cancer patients, the p.A459D mutation was identified once, in homozygosity (allele frequency 0.1%). No p.A459D mutations were identified in the control individuals. In vitro cleavage assay showed significantly reduced repair activity in p.A459D cells. Interestingly, another variant in the same codon has previously been described in a British study, supporting a key role for the codon 459 in MYH function. We therefore suggest that screening of mutations in MYH exon 14 should be added to the molecular analysis at-risk individuals.

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“…However, ethnic and geographic differences in the mutation spectrum have been observed. 14,17,20,25 We cannot rule out that we missed some mutations not detectable by routine procedures, in particular large genomic deletions. However, because of the low incidence of monoallelic MUTYH mutations in our polyposis patients, it is not very likely that these variants contribute substantially to the mutation spectrum and incidence of MUTYH.…”

Section: Spectrum Of Biallelic Mutyh Mutationsmentioning

confidence: 95%

“…To date, the impact of MUTYH mutations has been examined in patients with different phenotypes including FAP, MCA, HNPCC and sporadic CRC. 12,[14][15][16][17][18][19][20][21] However, several reports are restricted to the mutational hot spots and to selected patient samples; thus, the results vary considerably depending on inclusion criteria, methods used for mutation detection and ethnic background of the patients. Accordingly, there is still limited information about the general frequency of MUTYH mutations among patients with MCA.…”

mentioning

confidence: 99%

MUTYH‐associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype

Aretz

Uhlhaas

Goergens

et al. 2006

Intl Journal of Cancer

186

130

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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. ' 2006 Wiley-Liss, Inc.

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Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas

Abstract: Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently

Cited by 90 publications

References 22 publications

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

A novel functionally deficientMYH variant in individuals with colorectal adenomatous polyposis

MUTYH‐associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype

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