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

Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer. In contrast to the classic dominant condition of familial adenomatous polyposis (FAP) due to germinal mutations in the APC gene, the MYH polyposis is an autosomal recessive disease. The identification of individuals affected by MYH polyposis brings new and important implications for the diagnostic, screening, genetic counseling, follow up and therapeutic options in these patients. In this study, screening for germinal mutations in the MYH gene was performed in 53 Portuguese individuals with multiple colorectal adenomas or classic adenomatous polyposis, in whom no mutation had been identified in the APC gene. The results revealed the presence of biallelic germline MYH mutations in 21 patients. In addition, we here report 3 mutations (c.340T>C [p.Y114H]; c.503G>A [p.R168H]; and c.1186_1187insGG [p.E396fsX437]) which, to our knowledge, have not been previously described.

Isidro G ，Laranjeira F ，Pires A ，Leite J ，Regateiro F ，Castro e Sousa F ，Soares J ，Castro C ，Giria J ，Brito MJ ，Medeira A ，Teixeira R ，Morna H ，Gaspar I ，Marinho C ，Jorge R ，Brehm A ，Ramos JS ，Boavida MG ... -  《-》

Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.

Lejeune S ，Guillemot F ，Triboulet JP ，Cattan S ，Mouton C ，PAFNORD Group ，Porchet N ，Manouvrier S ，Buisine MP ... -  《-》

Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients.

MYH is a member of the DNA base excision repair (BER) pathway and mutations of this gene predispose to the development of colorectal neoplasia in an autosomal recessive transmission pattern. Our objective was to determine the significance of MYH mutations in a series of Canadian patients with multiple adenomas. We screened for germline MYH mutations (by dHPLCO) in 20 clinic-based multiple adenoma patients who were adenomatous polyposis coli (APC) mutation-negative. Suspected mutations were confirmed by sequence analysis. Six of 20 (30%) patients carried pathogenic biallelic MYH mutations, 1 Y165C homozygote and 5 compound heterozygotes of other sequence variants. We identified three novel variants, Q377X, 1314delA, and P281L, which are likely pathogenic. Twenty-nine relatives of the Y90X/1103delC compound heterozygous carrier were also screened for germline MYH mutations, and 1 homozygous and 14 heterozygous carriers were identified. Among patients with multiple adenomas, biallelic MYH mutations account for approximately 30% of APC mutation negative cases and two thirds of these carry mutations other than the "common" Y165C and G382D variants. Clinical screening algorithms which focus only on the Y165C and G382D alleles are inadequate since additional pathogenic mutations may be identified by screening the entire gene.

Croitoru ME ，Cleary SP ，Berk T ，Di Nicola N ，Kopolovic I ，Bapat B ，Gallinger S ... -  《JOURNAL OF SURGICAL ONCOLOGY》

Molecular analysis of the APC and MYH genes in Czech families affected by FAP or multiple adenomas: 13 novel mutations.

Familial adenomatous polyposis (FAP) is an autosomal dominant predisposition to colorectal cancer and is caused by germline mutations in the adenomatous polyposis coli gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps. A milder phenotype is found in patients affected with AFAP/ multiple adenomas. We screened the entire APC coding region using the combination of DGGE, PTT and direct sequencing and identified causative mutations in 52 of 77 patients. Thirteen of the mutations found were novel. In addition, we also tested 21 APC mutation/negative probands for the two most common mutations in the MYH gene. Four patients showed neither dominant transmission of the disease nor evidence of APC mutations. In one of them the most common biallelic germline mutation in the MYH gene was detected. Correlations between the localization of germline mutations and clinical manifestations of the diseases are discussed.

Vandrovcová J ，Stekrová J ，Kebrdlová V ，Kohoutová M ... -  《-》

The first mutations in the MYH gene reported in Moroccan colon cancer patients.

Biallelic germline mutations in the MYH gene cause MYH-associated polyposis (MAP) disease, an autosomal recessive form of inherited colorectal cancer. People with MAP tend to develop attenuated multiple adenomatous colon polyps during their lifetime and will have an increased risk of colorectal cancer. Contrary to familial adenomatous polyposis, the number of adenomas is often lower in MAP (from 5 to 100), and even some patients have recently been reported with no identified adenomas. There have been many investigations into MAP that have been conducted in many different countries. Currently there is limited data on MAP in Morocco, and it is reasonable to think, that the prevalence of this form of genetic predisposition is as high as other autosomal recessive genetic diseases found in countries with high rates of consanguinity. The aim of this study is to examine the frequency of MYH mutations in colorectal cancer and/or attenuated polyposis in Moroccan patients. The study population consisted of 62 patients; 52 with colorectal cancer, three of them had attenuated polyposis (2 to 99 adenomatous polyps). 10 other patients were referred to our department for polyposis without colorectal cancer. We carried out DNA analysis in 62 patients to screen for the three recurrent mutations c.494A>G (p.Tyr165Cys), c.1145G>A (p.Gly382Asp) and c.1185_1186dup, p.Glu396GlyfsX43, whereas 40 subjects were screened for germline MYH mutations in the whole coding sequence of the MYH gene by direct DNA sequencing. All these 40 patients, except two, had colorectal cancer without polyposis. Three patients with colorectal cancer and attenuated polyposis carried biallelic mutations in the MUTYH gene one with the c.494 A>G mutation, one with the c.1105delC mutation, one with the c.1145G>A mutation. One patient with 25 adenomas without colorectal cancer carried the c.1145G>A mutation at a homozygote state and one patient with 3 polyps was heterozygote for the mutation c.1145G>A. No biallelic mutations of MYH gene were detected in colorectal cancer patients and in patients with small number (<5) of polyps without colorectal cancer. We report the first biallelic MYH mutations in four Moroccan patients with clinical criteria of MAP; three of them had colorectal cancer with attenuated polyposis. No MYH mutations were found in colorectal patients without polyposis. Despite the relatively small sample size of the current study, our findings suggest that the MAP is not a frequent cause of colon cancer in Morocco as we had expected, and the molecular analysis of MYH gene should be restricted to patients displaying the classical phenotype of MAP.

Laarabi FZ ，Cherkaoui Jaouad I ，Baert-Desurmont S ，Ouldim K ，Ibrahimi A ，Kanouni N ，Frebourg T ，Sefiani A ... -  《-》