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• W2016009581 abstract "Background & Aims: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. Methods: The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. Results: In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. Conclusions: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis. Background & Aims: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. Methods: The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. Results: In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. Conclusions: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis. MYH-associated polyposis (MAP) is a recently described autosomal-recessive disease. On clinical grounds, patients with MAP frequently show features of attenuated polyposis, with a number of polyps ranging between 20 and 100.1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar, 2Jones S. Emmerson P. Maynard J. Best J.M. Jordan S. Williams G.T. Sampson J.R. Cheadle J.P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C>T:A mutations.Hum Mol Genet. 2002; 23: 2961-2967Crossref Google Scholar, 3Sieber O.M. Lipton L. Crabtree M. Heinimann K. Fidalgo P. Phillips R.K. Bisgaard M.L. Orntoft T.F. Aaltonen L.A. Hodgson S.V. Thomas H.J. Tomlinson I.P. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003; 348: 791-799Crossref PubMed Scopus (737) Google Scholar However, MAP also has been described in association with full-blown polyposis4Sampson J.R. Dolwani S. Jones S. Eccles D. Ellis A. Evans D.G. Frayling I. Jordan S. Mather E.R. Mak T. Maynard J. Pigatto F. Shaw J. Cheadle J.P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar and in patients with multiple polyps.5Jo W.S. Bandipalliam P. Shannon K.M. Niendorf K.B. Chan-Smutko G. Hur C. Syngal S. Chung D.C. Correlation of polyp number and family history of colon cancer with germline MYH mutations.Clin Gastroenterol Hepatol. 2005; 3: 1022-1028Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Patients with MAP have biallelic mutations in the base excision repair gene MYH and are negative for germline mutations in the APC gene.1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar, 2Jones S. Emmerson P. Maynard J. Best J.M. Jordan S. Williams G.T. Sampson J.R. Cheadle J.P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C>T:A mutations.Hum Mol Genet. 2002; 23: 2961-2967Crossref Google Scholar, 3Sieber O.M. Lipton L. Crabtree M. Heinimann K. Fidalgo P. Phillips R.K. Bisgaard M.L. Orntoft T.F. Aaltonen L.A. Hodgson S.V. Thomas H.J. Tomlinson I.P. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003; 348: 791-799Crossref PubMed Scopus (737) Google Scholar, 4Sampson J.R. Dolwani S. Jones S. Eccles D. Ellis A. Evans D.G. Frayling I. Jordan S. Mather E.R. Mak T. Maynard J. Pigatto F. Shaw J. Cheadle J.P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 5Jo W.S. Bandipalliam P. Shannon K.M. Niendorf K.B. Chan-Smutko G. Hur C. Syngal S. Chung D.C. Correlation of polyp number and family history of colon cancer with germline MYH mutations.Clin Gastroenterol Hepatol. 2005; 3: 1022-1028Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Enholm S. Hienonen T. Suomalainen A. Lipton L. Tomlinson I. Karja V. Eskelinen M Mecklin J.P. Karhu A. Jarvinen H.J. Aaltonen L.A. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients.Am J Pathol. 2003; 163: 827-832Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 7Isidro G. Laranjera F. Pires A. Leite J. Regateiro F. Castro e Sousa F. Soares J. Castro C. Giria J. Brito M.J. Medeira A. Teixeira R. Morna H. Gasper I. Marinho C. Jorge R. Brehm A. Ramos J.S. Boavida M.G. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas.Hum Mutat. 2004; 24: 353-354Crossref PubMed Scopus (81) Google Scholar, 8Croitoru M.E. Cleary S.P. Di Nicola N. Manno M. Selander T. Aronson M. Redston M. Cotterchio M. Knight J. Gryfe R. Gallinger S. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Natl Cancer Inst. 2004; 96: 1631-1634Crossref PubMed Scopus (220) Google Scholar, 9Gismondi V. Meta M. Bonelli L. Radice P. Sala P. Bertario L. Viel A. Fornasarig M. Arrigoni A. Gentile M. Ponz de Leon M. Anselmi L. Mareni C. Bruzzi P. Varesco L. Prevalence of the Y165 C, G382D and 1395delGCA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.Int J Cancer. 2004; 109: 680-684Crossref PubMed Scopus (138) Google Scholar, 10Venesio T. Molatore S. Cattaneo F. Arrigoni A. Risio M. Ranzani G.N. High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.Gastroenterology. 2004; 126: 1681-1685Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar MYH takes part in the base excision repair pathway, which plays a role in the repair of DNA damage caused by reactive oxygen species generated during the aerobic metabolism, and by exogenous stimuli, such as ionizing radiation and various chemical oxidants. It has been shown that human MutY omolog (hMYH) interacts physically with human MutS omolog (hMSH6), and that the MSH2–MSH6 heterodimer stimulates the DNA binding and glycosylase activities of MYH with an adenine:8-oxoguanine (A/GO) mismatch.11Parker A. Gu Y. Mahoney W. Lee S.H. Singh K.K. Lu A.L. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long-patch DNA base excision repair.J Biol Chem. 2001; 276: 5547-5555Crossref PubMed Scopus (195) Google Scholar, 12Boldogh I. Milligan D. Lee M.S. Bassett H. Lloyd R.S. McCullough A.K. hMYH cell cycle-dependent expression, subcellular localization and association with replication foci evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs.Nucleic Acids Res. 2001; 29: 2802-2809Crossref PubMed Scopus (131) Google Scholar There are few immunohistochemical studies of the MYH protein, which is expressed in mitochondria and in the nuclei and cytoplasm of normal human cells.13NakabeppuY Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage.Prog Nucleic Acid Res Mol Biol. 2001; 68: 75-94Crossref PubMed Google Scholar, 14Parker A.R. Eshleman J.R. Human MutY gene structure, protein functions and interactions, and role in carcinogenesis.Cell Mol Life Sci. 2003; 60: 2064-2083Crossref PubMed Scopus (57) Google Scholar A previous report described immunohistochemical expression of DNA repair proteins, including MYH, in colorectal carcinomas.15Koketsu S. Watanabe T. Nagawa H. Expression of DNA repair protein MYH, NTH1, and MTH1 in colorectal cancer.Hepatogastroenterology. 2004; 51: 638-642PubMed Google Scholar In familial gastric cancer, a splice variant of MYH gene, IVS10-2A > G, caused the production of a truncated protein localized in the cytoplasm, in contrast with the nuclear localization of the wild-type MYH protein.16Tao H. Shinmura K. Hanaoka T. Natsukawa S. Shaura K. Koizumi Y. Kasuga Y. Ozawa T. Tsujinaka T. Li Z. Yamaguchi S. Yokota J. Sugimura H. Tsugane S. A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus.Carcinogenesis. 2004; 25: 1859-1866Crossref PubMed Scopus (50) Google Scholar We studied, by immunohistochemistry, the expression pattern of the MYH protein in adenomas and colorectal cancers of patients with biallelic MYH mutation, in adenomas and carcinomas from patients carrying APC germline mutations, and in sporadic colorectal neoplasms and in normal colon mucosa from cancer-free individuals. The aim of this study was to evaluate whether an immunohistochemical approach could be used in clinical practice to identify patients carrying germline mutations in the MYH gene and to improve and render less expensive screening procedures. The study included 20 samples (adenomas or colorectal cancer) from 18 patients carrying MYH-biallelic mutations, 11 samples (8 adenomas and 3 carcinomas) from 7 familial adenomatous polyposis (FAP) and 4 attenuated familial adenomatous polyposis (AFAP) patients with different APC germline mutations (the list of APC mutations is shown in Table 1), and 20 samples from sporadic colorectal carcinomas and 10 samples of normal colon mucosa from patients without cancer. Samples were collected in 3 different centers (National Cancer Institute, Milano, Italy; Institute for Cancer Research and Treatment, Candiolo, Italy; and the Department of Internal Medicine, Modena, Italy).Table 1APC Mutations and Clinical Features of FAP/AFAP PatientsPatientSexAge, yAnalyzed sampleGradingSiteAPC mutationsaMutations are reported as nucleotides where alterations occur; for patients 6, 7, and 8 mutations are reported as codons where a nucleotide substitution introduces a stop for the protein transduction.1M36Tubular adenomaMildColon2553–2254 insA2M25Tubular adenomaMildColon2734 delT3F37Tubular adenomaMildColon2101–2102 insT4F19Tubular adenomaMildColon3496–3497 insA5F30Adenocarcinoma (Dukes’ B)WellColon4147delT6bAFAP patients.M37Tubular adenomasModerateColonS1032X7bAFAP patients.M31Adenocarcinoma (Dukes’ B)WellRectumY935X8bAFAP patients.F40Tubulovillous adenomasMildColonR1450X9bAFAP patients.M32Tubular adenomasMildColon3927 del510M19Tubular adenomasMildColon2893 del411F30Adenocarcinoma (Dukes’ B)ModerateRectum3927 del5a Mutations are reported as nucleotides where alterations occur; for patients 6, 7, and 8 mutations are reported as codons where a nucleotide substitution introduces a stop for the protein transduction.b AFAP patients. Open table in a new tab Germ-line MYH hot spots in exons 7, 13, and 14 and the whole coding region of the MYH gene were analyzed as already reported.9Gismondi V. Meta M. Bonelli L. Radice P. Sala P. Bertario L. Viel A. Fornasarig M. Arrigoni A. Gentile M. Ponz de Leon M. Anselmi L. Mareni C. Bruzzi P. Varesco L. Prevalence of the Y165 C, G382D and 1395delGCA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.Int J Cancer. 2004; 109: 680-684Crossref PubMed Scopus (138) Google Scholar, 10Venesio T. Molatore S. Cattaneo F. Arrigoni A. Risio M. Ranzani G.N. High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.Gastroenterology. 2004; 126: 1681-1685Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Exon 7, in which the Y165C mutation is located, was examined in all samples by direct sequencing and by the Amplification Refractory Mutation System, as described by Al-Tassan et al.1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar Exon 13, in which the G382D mutation was found, was examined in all samples by direct sequence or BglII digestion. Exon 14, in which 1395delGGA is located, was examined on an ABI PRISM (PE, Applied Biosystems, Foster City, CA) 310 Genetic Analyzer using GeneScan Analysis. The presence of 1395delGGA was confirmed by sequence analysis. The remaining coding region of the MYH gene was analyzed by direct sequencing. Immunohistochemical analysis of MYH, MSH2, MLH1, and MSH6 proteins was performed on paraffin-embedded tumor samples. The sections were cut into superfrost plus microscope slides and allowed to dry at 37°C overnight. The slides were submitted to antigen retrieval using macrowave in 10 mmol/L citrate buffer, pH 6, at 350 W for 30 minutes. Immunoperoxidase staining, using diaminobenzidine as a chromogen, was performed with the NEX-ES Automatic Staining System (Ventana, Strasbourg, France). Polyclonal antibody anti-MYH (Abcam, Cambridge, England) at 1:50 and monoclonal antibodies anti-MSH6 (Clone 44; Transduction Laboratories, BD Biosciences, Franklin Lakes, NJ) at 1:2000, anti-MLH1 (G168–15; Pharmingen, San Diego, CA) at 1:40, anti-MSH2 (G129–1129; Pharmingen) at 1:40 were used. Nuclei were counterstained with hematoxylin. Lack of expression of mismatch repair proteins was defined as complete absence of detectable nuclear staining in tumor cells. Intact nuclear staining of the colonic crypts of the peritumoral normal mucosa and lymphocytes served as internal positive control and was required for an adequate evaluation. Normal immunoreactivity of the MYH protein was defined as the presence of nuclear and cytoplasmic staining. MYH expression was evaluated by the scoring system reported by Gao et al17Gao D. Wei C. Chen L. Huang J. Yang S. Diehl A.M. Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease.Am J Physiol. 2004; 287: 1070-1077Crossref Scopus (280) Google Scholar: 0 = no staining, 1 = minimal or mild staining (10%–50% of positive cells), and 2 = strong staining (>50% of positive cells). The intensity of cytoplasmic immunostaining was classified according to a 2-grade scale of strong (++) or weak (+) staining.15Koketsu S. Watanabe T. Nagawa H. Expression of DNA repair protein MYH, NTH1, and MTH1 in colorectal cancer.Hepatogastroenterology. 2004; 51: 638-642PubMed Google Scholar Altered expression was considered when the cells showed cytoplasmic expression and absence of nuclear staining.16Tao H. Shinmura K. Hanaoka T. Natsukawa S. Shaura K. Koizumi Y. Kasuga Y. Ozawa T. Tsujinaka T. Li Z. Yamaguchi S. Yokota J. Sugimura H. Tsugane S. A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus.Carcinogenesis. 2004; 25: 1859-1866Crossref PubMed Scopus (50) Google Scholar The main clinical features of patients with MAP and the carrying MYH biallelic germline mutations are shown in Table 2. In this set the most frequent mutations were Y165C, G382D, and 1395delGGA, located at exons 7, 13, and 14, respectively. However, other types of alterations were found at exons 3, 7, 12, 13, and also at introns 6 and 10. Five patients were carriers of homozygous biallelic mutations, although all other cases were compound heterozygous. In all samples analyzed, the proteins encoded by the main DNA mismatch repair genes (MSH2, MLH1, and MSH6) were expressed normally.Table 2Clinical Features of Patients With MAP and the Type Biallelic MutationsPatientSexAge, yNo. adenomasDiagnosis/stageGradingSiteSizeMut MYH1M58>100Tubular adenomaMildDescending.5 cmG382D/1395delGGAA2F5790Adenocarcinoma (Dukes’ B)WellCecum6 cmY165C/Y165C3M45>100Adenocarcinoma (Dukes’ B)ModerateSigmoid6.2 cm1395delGGA/1395delGGA4M51<100Tubular adenomasMildRectumFragmentsG382D/1395delGGA2 samples5M56>100Adenocarcinoma (Dukes’ B)MucinousRectum3 cmY165C/Y165C6F51>100Tubulovillous adenomaMildColonFragmentsY165C/Y165C7M37>100Adenocarcinoma (Dukes’ B)ModerateDescending2.5 cm1395delGGA/Y90X2 samples8F52<100Tubulovillous adenomaMildColon1.3 cmY90X/IVS10 + 3A > C9M41>100Tubular adenomaMildAscending2.3 cm1395delGGA/1395delGGA10F5717Tubular adenomaMildColon.5 cmIVS6 + 19-31del13/IVS6 + 19-31del1311F57<100Adenocarcinoma (Dukes’ B)PoorCecum3.3 cmY165C/R168C12M35100Tubulovillous adenomaMildAscending2.5 cmY190X/W160X13F5170Adenocarcinoma (Dukes’ A)ModerateSigmoid2.8 cmG382D/1187insGC14F6540–50Tubulovillous adenomaMildDescending.3 cm199GT/1103delC15F5840–50Tubular adenomaMildCecum.5 cmY615C/G382D16F3450–70Tubular adenomaMildDescending.6 cm1103delC/G382D17F3240–50Adenocarcinoma (Dukes’ B)MucinousAscending3 cmR168H/379delC18F43>100Tubular adenomaMildAscendingFragmentsY90X/IVS10 + 3A > C Open table in a new tab Samples of normal colorectal mucosa (taken from individuals unaffected by colorectal neoplasia and not belonging to families with a history of colorectal cancer) showed both nuclear and cytoplasmic immunoreactivity for the MYH protein in all colonocytes (Figure 1). The intensity of cytoplasmic immunostaining was always weak. Nuclear and cytoplasmic expression of MYH protein was observed in all samples of sporadic colorectal carcinomas, both in the tumoral portion and in the surrounding normal mucosa. Moreover, a positive reaction was seen in the majority (>50%) of cells. The cytoplasmic immunostaining was defined as strong in 13 of these cases, and weak in the remaining 7 (Figure 2). Similarly, in adenomas and carcinomas from patients with different APC germline mutations, nuclear and cytoplasmic expression of MYH were observed, as shown in Figure 3.Figure 2Nuclear and weak cytoplasmic expression of MYH protein in sporadic colorectal cancer (original magnification, 40×).View Large Image Figure ViewerDownload (PPT)Figure 3Nuclear and weak cytoplasmic expression of MYH protein in an adenoma of a FAP patient with APC germline mutation (original magnification, 20×).View Large Image Figure ViewerDownload (PPT) Adenomas and carcinomas from patients with MYH biallelic mutations showed a different pattern of expression. Immunoreactivity for the MYH protein could be detected in all cases (n = 18); however, at variance with sporadic tumors and colorectal mucosa from normal individuals, a strong granular cytoplasmic staining was observed, without any nuclear expression of the protein. As shown in Figure 4 the immunoreactivity was localized at the apex of the neoplastic cells. Moreover, adjacent normal mucosa—in patients with biallelic MYH mutations—showed the same pattern of expression found in adenomas and carcinomas (ie, strong cytoplasmic immunoreactivity and absence of nuclear expression) (Figure 5).Figure 5Strong cytoplasmic immunoreactivity and absence of nuclear expression of MYH protein in normal mucosa of a patient with a biallelic MYH mutation (original magnification, 20×).View Large Image Figure ViewerDownload (PPT) The results of the present study allow a definition of the MYH protein expression pattern in normal conditions, in sporadic neoplasms, in tumors associated with APC mutations, and in tumors from patients with biallelic MYH mutations. In normal mucosa of the large bowel from healthy donors belonging to families without a history of colorectal cancer and in common colorectal neoplasms and in tumors from FAP or AFAP patients with APC germline mutations, the immunoreactivity for MYH is localized both in the nucleus and in the cytoplasm of colonocytes or tumoral cells. This indicates that the protein encoded by the gene exerts its functions in various cellular domains. In contrast, neoplasms and surrounding healthy mucosa from patients with biallelic mutations, independently of the type (homozygous or compound heterozygous; missense or deletions/insertion) and position, show disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm. This finding is consistent with the fact that all cells of these patients carry 2 germline MYH mutations, and indicates that despite the biallelic mutation the MYH polypeptide still is synthesized and presumably exerts some functions in the cytoplasm. The reasons for this altered distribution and peculiar compartmentalization of immunostaining in the presence of biallelic MYH mutations remain unclear, the protein produced by the mutated gene could lack the capacity to transfer into the nucleus and remain trapped in the cytoplasm. The role of MYH in colorectal tumorigenesis was suggested by the seminal work of Al-Tassan et al1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar in 2002. These and other investigators1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar, 2Jones S. Emmerson P. Maynard J. Best J.M. Jordan S. Williams G.T. Sampson J.R. Cheadle J.P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C>T:A mutations.Hum Mol Genet. 2002; 23: 2961-2967Crossref Google Scholar, 3Sieber O.M. Lipton L. Crabtree M. Heinimann K. Fidalgo P. Phillips R.K. Bisgaard M.L. Orntoft T.F. Aaltonen L.A. Hodgson S.V. Thomas H.J. Tomlinson I.P. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003; 348: 791-799Crossref PubMed Scopus (737) Google Scholar, 4Sampson J.R. Dolwani S. Jones S. Eccles D. Ellis A. Evans D.G. Frayling I. Jordan S. Mather E.R. Mak T. Maynard J. Pigatto F. Shaw J. Cheadle J.P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 5Jo W.S. Bandipalliam P. Shannon K.M. Niendorf K.B. Chan-Smutko G. Hur C. Syngal S. Chung D.C. Correlation of polyp number and family history of colon cancer with germline MYH mutations.Clin Gastroenterol Hepatol. 2005; 3: 1022-1028Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Enholm S. Hienonen T. Suomalainen A. Lipton L. Tomlinson I. Karja V. Eskelinen M Mecklin J.P. Karhu A. Jarvinen H.J. Aaltonen L.A. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients.Am J Pathol. 2003; 163: 827-832Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 7Isidro G. Laranjera F. Pires A. Leite J. Regateiro F. Castro e Sousa F. Soares J. Castro C. Giria J. Brito M.J. Medeira A. Teixeira R. Morna H. Gasper I. Marinho C. Jorge R. Brehm A. Ramos J.S. Boavida M.G. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas.Hum Mutat. 2004; 24: 353-354Crossref PubMed Scopus (81) Google Scholar, 8Croitoru M.E. Cleary S.P. Di Nicola N. Manno M. Selander T. Aronson M. Redston M. Cotterchio M. Knight J. Gryfe R. Gallinger S. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Natl Cancer Inst. 2004; 96: 1631-1634Crossref PubMed Scopus (220) Google Scholar found that a proportion of FAP (or AFAP) patients negative for APC constitutional mutations, and patients with multiple polyps, had germline mutations in the base excision repair gene MYH. At the same time, 2 studies showed that MAP may account for 20%–35% of Italian FAP/AFAP patients negative for the presence of constitutional mutations of the APC gene and with no vertical transmission of the disease.9Gismondi V. Meta M. Bonelli L. Radice P. Sala P. Bertario L. Viel A. Fornasarig M. Arrigoni A. Gentile M. Ponz de Leon M. Anselmi L. Mareni C. Bruzzi P. Varesco L. Prevalence of the Y165 C, G382D and 1395delGCA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.Int J Cancer. 2004; 109: 680-684Crossref PubMed Scopus (138) Google Scholar, 10Venesio T. Molatore S. Cattaneo F. Arrigoni A. Risio M. Ranzani G.N. High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.Gastroenterology. 2004; 126: 1681-1685Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar The 2 mutations described by Al-Tassan et al1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar (Y165C and G328D) were also the most frequent in Italian patients with MAP. These mutations affect amino acid residues highly conserved throughout evolution, and attenuate consistently the enzymatic activity of an equivalent protein in Escherichia coli.1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar Immunohistochemical studies on the expression of MYH protein are scanty. In 2004, Koketsu et al15Koketsu S. Watanabe T. Nagawa H. Expression of DNA repair protein MYH, NTH1, and MTH1 in colorectal cancer.Hepatogastroenterology. 2004; 51: 638-642PubMed Google Scholar evaluated the expression of this protein in a series of unselected colorectal neoplasms; the investigators reported the presence of immunoreactivity in nuclei and cytoplasm, with marked expression in 57% of patients. Tao et al16Tao H. Shinmura K. Hanaoka T. Natsukawa S. Shaura K. Koizumi Y. Kasuga Y. Ozawa T. Tsujinaka T. Li Z. Yamaguchi S. Yokota J. Sugimura H. Tsugane S. A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus.Carcinogenesis. 2004; 25: 1859-1866Crossref PubMed Scopus (50) Google Scholar described an interesting gastric cancer family in which no biallelic mutations were detected but a novel splice-site variant was found that caused the production of a truncated protein localized in the cytoplasm. This contrasts with the nuclear localization of the wild-type MYH protein and suggests that the excisional repair ability of the variant-type MYH protein could be impaired. This also might occur in MYH-associated colorectal polyposis, in which immunostaining is limited to the cytoplasm and disappears from the nucleus (which is the site of DNA repair machinery). It is interesting to compare MAP with hereditary nonpolyposis colorectal cancer18Lynch H.T. Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An update review.Cancer. 1996; 78: 1149-1167Crossref PubMed Scopus (473) Google Scholar because both diseases implicate defects in the DNA repair mechanisms.19Halford S.E.R. Rowan A.J. Lipton L. Sieber O.M. Pack K. Thomas H.J.W. Hodgson S.V. Bodmer W.F. Tomlinson I.P.M. Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers.Am J Pathol. 2003; 162: 1545-1548Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar For hereditary nonpolyposis colorectal cancer, however, in patients with constitutional mutations of MSH2, MLH1, or MSH6 genes the somatic inactivation of a second allele during tumor development results in loss of protein expression and in generalized DNA mismatch repair deficiency, which is associated with tumor occurrence in some target organs. It is well established that lack of protein expression—detected by immunohistochemistry—correlates with microsatellite instability; thus, the immunohistochemical analysis is useful in selecting individuals and families to be screened for constitutional mutations.20Hampel H. Frankel W.L. Martin E. Arnold M. Khanduja K. Kuebler P. Nakagawa H. Sotamaa K. Prior T.W. Westman J. Panescu J. Fix D. Lockman J. Comeras I. de la Chapelle A. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).N Engl J Med. 2005; 352: 1851-1860Crossref PubMed Scopus (1123) Google Scholar In contrast, in MYH polyposis, despite homozygous or compound heterozygous mutations, the MYH protein is expressed, but disappears from the nucleus and localizes in the cytoplasm. Because this pattern of expression is rather indicative of biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MAP. It has recently been suggested that the interaction between the MYH protein and the MSH2/MSH6 heterodimer may be a means by which MYH repair cooperates in reducing replicative errors caused by oxidized bases.11Parker A. Gu Y. Mahoney W. Lee S.H. Singh K.K. Lu A.L. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long-patch DNA base excision repair.J Biol Chem. 2001; 276: 5547-5555Crossref PubMed Scopus (195) Google Scholar, 12Boldogh I. Milligan D. Lee M.S. Bassett H. Lloyd R.S. McCullough A.K. hMYH cell cycle-dependent expression, subcellular localization and association with replication foci evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs.Nucleic Acids Res. 2001; 29: 2802-2809Crossref PubMed Scopus (131) Google Scholar In our patients with MYH mutations, the mismatch repair proteins (MSH2, MLH1, and MSH6) were expressed normally. It follows that the cytoplasmic expression of MYH protein does not seem to influence the immunohistochemical expression of MSH2 and MSH6 proteins. Bai et al21Bai H. Jones S. Guan X. Wilson T.M. Sampson J.R. Cheadle J.P. Lu A.-L. Functional characterization of the two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis.Nucleic Acids Res. 2005; 33: 597-604Crossref PubMed Scopus (59) Google Scholar recently showed in vitro that MYH missense mutations (R227W and V232F) lying within or adjacent to the putative MSH6 binding domain can result in a variable defect of repairing the A/8-OXOG mismatch, but they do not affect the physical interactions between MYH and MSH6. These findings suggest that even if the complex composed by MYH and MSH6/MSH2 has lost its enzymatic activity, it can be expressed normally. Thus, in conclusion, our results are consistent with the hypothesis that staining with antibodies specific for MYH protein could provide information on the possible role of this gene for tumor development in patients with FAP, attenuated polyposis,1Al-Tassan N. Chmiel N.H. Maynard J. Fleming N. Livingston A.L. Williams G.T. Hodges A.K. Davies D.R. David S.S. Sampson J.R. Cheadle J.P. Inherited variants of MYH associated with somatic G:C>T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1081) Google Scholar, 2Jones S. Emmerson P. Maynard J. Best J.M. Jordan S. Williams G.T. Sampson J.R. Cheadle J.P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C>T:A mutations.Hum Mol Genet. 2002; 23: 2961-2967Crossref Google Scholar, 3Sieber O.M. Lipton L. Crabtree M. Heinimann K. Fidalgo P. Phillips R.K. Bisgaard M.L. Orntoft T.F. Aaltonen L.A. Hodgson S.V. Thomas H.J. Tomlinson I.P. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003; 348: 791-799Crossref PubMed Scopus (737) Google Scholar, 4Sampson J.R. Dolwani S. Jones S. Eccles D. Ellis A. Evans D.G. Frayling I. Jordan S. Mather E.R. Mak T. Maynard J. Pigatto F. Shaw J. Cheadle J.P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 5Jo W.S. Bandipalliam P. Shannon K.M. Niendorf K.B. Chan-Smutko G. Hur C. Syngal S. Chung D.C. Correlation of polyp number and family history of colon cancer with germline MYH mutations.Clin Gastroenterol Hepatol. 2005; 3: 1022-1028Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Enholm S. Hienonen T. Suomalainen A. Lipton L. Tomlinson I. Karja V. Eskelinen M Mecklin J.P. Karhu A. Jarvinen H.J. Aaltonen L.A. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients.Am J Pathol. 2003; 163: 827-832Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 7Isidro G. Laranjera F. Pires A. Leite J. Regateiro F. Castro e Sousa F. Soares J. Castro C. Giria J. Brito M.J. Medeira A. Teixeira R. Morna H. Gasper I. Marinho C. Jorge R. Brehm A. Ramos J.S. Boavida M.G. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas.Hum Mutat. 2004; 24: 353-354Crossref PubMed Scopus (81) Google Scholar, 8Croitoru M.E. Cleary S.P. Di Nicola N. Manno M. Selander T. Aronson M. Redston M. Cotterchio M. Knight J. Gryfe R. Gallinger S. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Natl Cancer Inst. 2004; 96: 1631-1634Crossref PubMed Scopus (220) Google Scholar atypical Muir–Torre syndrome,22Ponti G. Ponz de Leon M. Maffei S. Pedroni M. Losi L. Di Gregorio C. Gismondi V. Scarselli A. Benatti P. Roncari B. Seidenari S. Pellacani G. Varotti C. Prete E. Varesco L. Roncucci L. Attenuated familial adenomatous polyposis and Muir Torre Syndrome linked to compound biallelic constitutional MYH gene mutations.Clin Genet. 2005; 68: 442-447Crossref PubMed Scopus (67) Google Scholar or even common patients (individuals with polyps apparently not related to gene mutations) with multiple adenomas, with or without carcinoma of the large bowel.4Sampson J.R. Dolwani S. Jones S. Eccles D. Ellis A. Evans D.G. Frayling I. Jordan S. Mather E.R. Mak T. Maynard J. Pigatto F. Shaw J. Cheadle J.P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 23Fleischmann C. Peto J. Cheadle J. Shah B. Sampson J. Houlston R.S. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer.Int J Cancer. 2004; 109: 554-558Crossref PubMed Scopus (99) Google Scholar The test is rather simple and can be performed in formalin-fixed, paraffin-embedded material; this means that a large number of patients can be investigated in a relatively short period of time and in a great variety of clinical conditions. Future investigations should clarify whether immunohistochemistry—as in the case of hereditary nonpolyposis colorectal cancer—could be used as a preliminary step toward the molecular diagnosis of MAP." @default.
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