MYH-Associated Disease: Attenuated Adenomatous Polyposis of the Colon Is Only Part of the Story
2009; Elsevier BV; Volume: 137; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2009.10.017
ISSN1528-0012
Autores Tópico(s)Colorectal Cancer Treatments and Studies
ResumoSee "Expanded extracolonic tumor spectrum in the MUTYH-associated polyposis," by Vogt S, Jones N, Christian D, et al, on page 1976. See "Expanded extracolonic tumor spectrum in the MUTYH-associated polyposis," by Vogt S, Jones N, Christian D, et al, on page 1976. MYH and Attenuated Adenomatous Polyposis Coli.MutY human homolog (MYH) encodes a critical member of the DNA base–excision–repair system. Oxidation of DNA leads to the formation of 8-oxo-7, 8-dihydroxy-2′-deoxygunosine. This nucleotide mispairs with adenine resulting in somatic G:C → T:A transversions. MYH is an adenine-specific DNA glycosylase that removes the mispaired adenines. MYH-associated disease was reported first by Al-Tassan et al1Al-Tassan N. Chmiel N.H. Maynard J. et al.Inherited variants of MYH associated with somatic G:C → T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1088) Google Scholar when they described a family with recessive inheritance of multiple colorectal adenomas and cancers. The tumors had an excess of G:C → T:A transversions in APC, the cause being biallelic germline mutations in MYH. Since that time other studies have confirmed that biallelic MYH mutations, either homozygous or compound heterozygous, can cause adenomatous polyposis of the colon similar to that seen among carriers of germline APC mutations.2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar Biallelic MYH mutations likely account for 30%–40% of adenomatous polyposis cases in which an APC mutation cannot be found.2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar, 3Wang L. Baudhuin L.M. Boardman L.A. et al.MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.Gastroenterology. 2004; 127: 9-16Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 4Artez S. Uhlhaas S. Goergens H. et al.MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.Int J Cancer. 2006; 119: 807-814Crossref PubMed Scopus (166) Google Scholar The most common MYH mutations in Western populations are Y179C or G396D, but many other disease-causing alleles have been described.5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google ScholarMYH-associated polyposis often has an attenuated phenotype in terms of age of onset and numbers of adenomas compared with classic familial adenomatous polyposis (FAP).2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar, 3Wang L. Baudhuin L.M. Boardman L.A. et al.MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.Gastroenterology. 2004; 127: 9-16Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 4Artez S. Uhlhaas S. Goergens H. et al.MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.Int J Cancer. 2006; 119: 807-814Crossref PubMed Scopus (166) Google Scholar, 5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Typically, an MYH-associated polyposis patient has a cumulative adenoma count of 15–100, with adenoma counts of >1000 having never been reported.2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar, 3Wang L. Baudhuin L.M. Boardman L.A. et al.MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.Gastroenterology. 2004; 127: 9-16Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 4Artez S. Uhlhaas S. Goergens H. et al.MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.Int J Cancer. 2006; 119: 807-814Crossref PubMed Scopus (166) Google Scholar, 5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Nevertheless, the lifetime risk for colorectal cancer (CRC) remains very high among the carriers of biallelic mutations. In clinic-based studies, risks as high as 93-fold for CRC, with almost complete penetrance by 60 years of age,6Farrington S.M. Tenesa A. Barnetson R. et al.Germline susceptibility to colorectal cancer due to base-excision repair gene defects.Am J Hum Genet. 2005; 77: 112-119Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar have been reported. With population-based case ascertainment, the risks for CRC are likely lower,5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 7Jenkins M.A. Croitoru M.E. Monga N. et al.Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.Cancer Epidemiol Biomarkers Prev. 2006; 15: 312-314Crossref PubMed Scopus (146) Google Scholar but remain substantial. In 1 recent such study, an 18-fold risk for CRC among homozygous/compound heterozygous MYH mutation carriers was found, with biallelic mutation carriers accounting for 0.7% of all CRC cases.5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar It also seems there may be a genotype–phenotype correlation with respect to cancer risk and age of onset, with homozygous Y179C mutation carriers having a more severe phenotype with respect to absolute cancer risk and age of onset compared with individuals who carry the G396D allele.8Nielsen M. Joerink-van de Beld M.C. Jones N. et al.Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis.Gastroenterology. 2009; 136: 471-476Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar MYH and Hyperplastic/Serrated Polyposis. The initial reports of MYH-associated polyposis described an attenuated version of adenomatous polyposis2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar; however, recent reports have indicated that the MYH-related polyps need not be traditional adenomas.9Chow E, Lipton L, Lynch E, et al. Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH.Google Scholar Boparai et al10Boparai K.S. Dekker E. van Eeden S. et al.Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.Gastroenterology. 2008; 135: 2014-2018Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar reported on a small series of 17 patients with MYH-associated polyposis, 8 of whom (47%) had serrated polyps.10Boparai K.S. Dekker E. van Eeden S. et al.Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.Gastroenterology. 2008; 135: 2014-2018Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Interestingly, G:C → T:A transversions in APC were found only in the traditional adenomas, while G:C → T:A transversions in K-ras were detected in 70% of the MYH-associated serrated polyps. It seems that the polyposis phenotype (traditional adenomatous polyposis vs serrated polyposis) depends on the target genes mutated and left unrepaired as a consequence of the loss of MYH function. The fundamental insight is that loss of base excision repair as a consequence of biallelic MYH mutations does not on its own strictly dictate the neoplastic phenotype; rather, it is the target genes that are mutated as a consequence of oxidative damage that matter.11Castells A. MYH-associated polyposis: adenomas and hyperplastic polyps, partners in crime?.Gastroenterology. 2008; 135: 1857-1859Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar MYH and CRC Without Polyposis. Although the initial reports of MYH-associated neoplasia in the colon focused on the occurrence of polyposis, it also has become clear that biallelic MYH mutations can lead to CRC in the absence of polyposis, or even any other polyps,3Wang L. Baudhuin L.M. Boardman L.A. et al.MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.Gastroenterology. 2004; 127: 9-16Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar albeit these CRCs often are of an earlier onset as compared with sporadic CRC. For example, in the report by Croitoru et al,12Croitoru M.E. Cleary S.P. Di Nicola N. et al.Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Nat Cancer Inst. 2004; 96: 1631-1634Crossref PubMed Scopus (220) Google Scholar 42% of the patients with MYH-associated CRC as a consequence of biallelic mutations had no more than 1 synchronous polyp, and Cleary et al5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar reported an absence of polyps in 35% of the cases at the time of the CRC diagnosis. There also is now convincing evidence that monoallelic germline MYH mutations increase the risk for CRC.5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The veracity of this finding had been called into question, with a recent systematic review by Balaguer et al13Balaguer F. Castellvi-Bel S. Castells A. et al.Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study.Gastroenterology. 2007; 5: 379-387Scopus (138) Google Scholar not finding an increased risk for CRC among monoallelic MYH mutation carriers (odds ratio, 1.11; 95% confidence interval [CI], 0.90–1.37). However, 2 very recent and exceptionally well done studies, one a large multicenter, population-based, case-control study by Cleary et al5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar and the other a multicenter registry-based study examining the CRC risk in obligate carriers of monoallelic MYH mutations by Jones et al,14Jones N. Vogt S. Nielsen M. et al.Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH.Gastroenterology. 2009; 137: 489-494Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar both found a clear increase incidence in CRCs among individuals with only a single germline MYH mutation. Cleary et al5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar found an adjusted odds ratio of 1.48 (95% CI, 1.02–2.16),5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar and Jones et al14Jones N. Vogt S. Nielsen M. et al.Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH.Gastroenterology. 2009; 137: 489-494Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar found a standardized incidence ratio of 2.12 (95% CI, 1.30–3.28). One of the additional fascinating findings of the study by Cleary et al5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar relates to the microsatellite instability (MSI) status of the MYH-related tumors. Approximately 20% of the MYH-associated CRCs, both in those with biallelic and monoallelic MYH mutations, were found to have low-frequency MSI (MSI-L), whereas MSI-L tumors were found in only 9% of MYH–wild-type cases. There was no evidence of an excess of high-frequency MSI (MSI-H) tumors among those with MYH mutations, but there was a strong association between being a MYH mutation carrier and developing an MSI-L CRC. The reason for this finding has not been elucidated, but it is known that some degree of MSI may be associated with CRCs arising via the serrated polyp pathway,15Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (1106) Google Scholar and that this molecular progression pathway may be a common one for MYH-related CRCs.10Boparai K.S. Dekker E. van Eeden S. et al.Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.Gastroenterology. 2008; 135: 2014-2018Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar MYH and Extracolonic Neoplasia. Like the mismatch repair genes, MYH is a DNA repair gene. It is to be expected that in the presence of base-excision repair deficiency mutations may occur in target genes from a variety of different molecular progression pathways, and as a consequence of this the spectrum of neoplasia associated with MYH mutations might not be limited to the colon. However, in contrast with colorectal neoplasia, there has been very little information available regarding the extracolonic manifestations of MYH-associated disease. Because the initial descriptions of MYH-associated disease focused on the similarities of the phenotype with attenuated FAP, most reports focused on the presence or absence of extracolonic features seen typically in FAP. Duodenal adenomas are far less common in patients with MYH-associated polyposis than in those with FAP, occurring in about 20%–25% of patients with biallelic MYH mutations.2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar, 4Artez S. Uhlhaas S. Goergens H. et al.MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.Int J Cancer. 2006; 119: 807-814Crossref PubMed Scopus (166) Google Scholar Other common extraintestinal features of FAP, such as gastric fundic gland polyps or desmoid tumors are even less commonly observed.2Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH.N Eng J Med. 2003; 348: 791-799Crossref PubMed Scopus (739) Google Scholar, 4Artez S. Uhlhaas S. Goergens H. et al.MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.Int J Cancer. 2006; 119: 807-814Crossref PubMed Scopus (166) Google Scholar More recently, a few provocative case reports have indicated that the spectrum of extracolonic lesions in MYH-associated disease might be far different from that observed in FAP, and in fact there are reports of the occurrence of neoplasias that are more characteristic of Lynch syndrome. For example, there have been recent reports of sebaceous neoplasms suggestive of the Muir–Torre syndrome occurring in patients with biallelic MYH mutations,16Ponti G. Ponz de Leon M. Maffei S. et al.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 although these lesions are microsatellite stable when MYH related. There also are reports of MYH-associated endometrial cancer.17Barneston R.A. Devlin L. Miller J. et al.Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer.Clin Genet. 2007; 72: 551-555Crossref PubMed Scopus (37) Google Scholar The study by Vogt et al18Vogt S. Jones N. Christian D. et al.Expanded extracolonic tumor spectrum in the MUTYH-associated polyposis.Gastroenterology. 2009; 137: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar that appears in this edition of Gastroenterology contributes greatly to our understanding of the full spectrum of MYH-associated disease. The investigators assembled a large cohort of patients with MYH-associated polyposis and they went on to collect detailed information regarding the extracolonic tumor spectrum and risk. The findings make it clear that extracolonic neoplasia among MYH mutation carriers is common, with a lifetime risk of 38%, but the disease spectrum is far different than seen in FAP.18Vogt S. Jones N. Christian D. et al.Expanded extracolonic tumor spectrum in the MUTYH-associated polyposis.Gastroenterology. 2009; 137: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Duodenal polyposis occurs in 15 adenomas and in nearly 10% of those with classic FAP with no APC mutation.Wang et al (2004)3Wang L. Baudhuin L.M. Boardman L.A. et al.MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps.Gastroenterology. 2004; 127: 9-16Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar1. Biallelic MYH mutations can lead to early onset CRC in the absence of polyposis.Boparai et al (2008)10Boparai K.S. Dekker E. van Eeden S. et al.Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.Gastroenterology. 2008; 135: 2014-2018Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar1. Serrated polyps occur in upwards of 50% of patients with MYH-associated polyposis.2. G:C → T:A transversions occur in different target genes when comparing traditional adenomas and serrated polyps (APC versus K-ras).Cleary et al (2009)5Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar1. Monoallelic germline MYH mutation increases the risk for CRC approximately 1.5-fold.2. Biallelic MYH mutations increase the risk for CRC nearly 20-fold, but account for <1% of all CRCs.3. A higher prevalence of low frequency MSI is observed in the CRCs of MYH mutation carriers.Vogt et al (2009)18Vogt S. Jones N. Christian D. et al.Expanded extracolonic tumor spectrum in the MUTYH-associated polyposis.Gastroenterology. 2009; 137: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar1. Duodenal polyposis and duodenal cancer occurs in biallelic MYH mutation carriers.2. Extraintestinal cancers occur in nearly 40% of biallelic MYH mutation carriers with a spectrum of disease far different than seen in FAP with an increased risk for ovarian, bladder, and skin cancers observed. Open table in a new tab Expanded Extracolonic Tumor Spectrum in MUTYH-Associated PolyposisGastroenterologyVol. 137Issue 6PreviewMUTYH-associated polyposis (MAP) is characterized by a lifetime risk of colorectal cancer of up to 100%. However, no systematic evaluation of extracolonic manifestations has been reported. Full-Text PDF
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