MLH1 epimutationの現状
MLH1 epimutation は，生殖細胞系列にMLH1 遺伝子のプロモーター領域のメチル化を認め，若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候群である．世代を越えての継承を認めるgermlineepimutation と認めないconstitutional epimutation に分類され，多くは後者に属する．MLH1 epimutation の大腸癌の多くは右側大腸に発生し，片側アレルのMLH1 遺伝子のプロモーター領域のメチル化と正常アレルの欠失によりMLH1 の発現が消失しMSI-H を示す．スクリーニングでは，改訂ベテスダガイドラインとMSI 検...
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| Published in | 家族性腫瘍 Vol. 14; no. 2; pp. 29 - 34 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本家族性腫瘍学会
2014
一般社団法人日本遺伝性腫瘍学会 The Japanese Society for Hereditary Tumors |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1346-1052 2189-6674 |
| DOI | 10.18976/jsft.14.2_29 |
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| Abstract | MLH1 epimutation は，生殖細胞系列にMLH1 遺伝子のプロモーター領域のメチル化を認め，若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候群である．世代を越えての継承を認めるgermlineepimutation と認めないconstitutional epimutation に分類され，多くは後者に属する．MLH1 epimutation の大腸癌の多くは右側大腸に発生し，片側アレルのMLH1 遺伝子のプロモーター領域のメチル化と正常アレルの欠失によりMLH1 の発現が消失しMSI-H を示す．スクリーニングでは，改訂ベテスダガイドラインとMSI 検査が重要であり，MSI-H の患者に対してはMMR 遺伝子の胚細胞変異を検索し，変異が認めない症例には，血液，癌組織のMLH1 遺伝子のプロモーター領域のメチル化の検索を行う必要がある．サーベイランスでは，リンチ症候群関連腫瘍のサーベーランスプログラムに従い異時性癌の発生に注意が必要である． |
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| AbstractList | MLH1 epimutationは, 生殖細胞系列にMLH1遺伝子のプロモーター領域のメチル化を認め, 若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候群である. 世代を越えての継承を認めるgermline epimutationと認めないconstitutional epimutationに分類され, 多くは後者に属する. MLH1 epimutationの大腸癌の多くは右側大腸に発生し, 片側アレルのMLH1遺伝子のプロモーター領域のメチル化と正常アレルの欠失によりMLH1の発現が消失しMSI-Hを示す. スクリーニングでは, 改訂ベテスダガイドラインとMSI検査が重要であり, MSI-Hの患者に対してはMMR遺伝子の胚細胞変異を検索し, 変異が認めない症例には, 血液癌組織のMLH1遺伝子のプロモーター領域のメチル化の検索を行う必要がある. サーベイランスでは, リンチ症候群関連腫瘍のサーベーランスプログラムに従い異時性癌の発生に注意が必要である. MLH1 epimutation は，生殖細胞系列にMLH1 遺伝子のプロモーター領域のメチル化を認め，若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候群である．世代を越えての継承を認めるgermlineepimutation と認めないconstitutional epimutation に分類され，多くは後者に属する．MLH1 epimutation の大腸癌の多くは右側大腸に発生し，片側アレルのMLH1 遺伝子のプロモーター領域のメチル化と正常アレルの欠失によりMLH1 の発現が消失しMSI-H を示す．スクリーニングでは，改訂ベテスダガイドラインとMSI 検査が重要であり，MSI-H の患者に対してはMMR 遺伝子の胚細胞変異を検索し，変異が認めない症例には，血液，癌組織のMLH1 遺伝子のプロモーター領域のメチル化の検索を行う必要がある．サーベイランスでは，リンチ症候群関連腫瘍のサーベーランスプログラムに従い異時性癌の発生に注意が必要である． |
| Author | 菅野, 康吉 宮倉, 安幸 安田, 是和 |
| Author_FL | Miyakura Yasuyuki Yasuda Yoshikazu Sugano Kokichi |
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| References | 3）Fishel R, Lescoe MK, Rao MR, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993 ; 75 : 1027–1038. 29）Goel A, Nguyen TP, Leung HC, et al.: De novo constitutional MLH1 epimutations confer earlyonset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer 2011 ; 128 : 869–878. 18）Suter CM, Martin DI, Ward RL : Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 2004 ; 36 : 497–501. 33）Chan TL, Yuen ST, Kong CK, et al.: Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 2006 ; 38 : 1178–1183. 15）Young J, Simms LA, Biden KG, et al.: Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 2001 ; 159 : 2107–2116. 20）Valle L, Carbonell P, Fernandez V, et al.: MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin Genet 2007 ; 71 : 232–237. 36）Koinuma K, Shitoh K, Miyakura Y, et al.: Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 2004 ; 108 : 237–242. 25）Hitchins MP, Rapkins RW, Kwok CT, et al.: Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5 ′UTR. Cancer Cell 2011 ; 20 : 200–213. 13）Miyakura Y, Sugano K, Konishi F, et al.: Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology 2001 ; 121 : 1300–1309. 5）Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994 ; 368 : 258–261. 10）Kane MF, Loda M, Gaida GM, et al.: Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997 ; 57 : 808–811. 31）Ward RL, Dobbins T, Lindor NM, et al.: Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet Med 2013 ; 15 : 25–35. 38）Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer（Lynch Syndrome） and Microsatellite Instability. J Natl Cancer Inst 2004; 96: 261–268. 19）Hitchins M, Williams R, Cheong K, et al.: MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 2005 ; 129 : 1392–1399. 35）Ligtenberg MJ, Kuiper RP, Geurts van Kessel A, Hoogerbrugge N : EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam Cancer 2013 ; 12 : 169–174. 27）Case AS, Zighelboim I, Mutch DG, et al.: Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. Gynecol Oncol 2008 ; 108 : 438–444. 2）Lynch HT, Lynch PM, Lanspa SJ, et al.: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009 ; 76 : 1–18. 28）Niessen RC, Hofstra RM, Westers H, et al.: Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 2009 ; 48 : 737–744. 32）Holliday R: The inheritance of epigenetic defects. Science 1987 ; 238 : 163–170. 8）Thibodeau SN, Bren G, Schaid D : Microsatellite instability in cancer of the proximal colon. Science 1993 ; 260 : 816–819. 14）Miyakura Y, Sugano K, Konishi F, et al.: Methylation profile of the MLH1 promoter region and their relationship to colorectal carcinogenesis. Genes Chromosomes Cancer 2003 ; 36 : 17–25. 30）Hitchins MP, Owens SE, Kwok CT, et al.: Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort. Clin Genet 2011 ; 80 : 428–434. 22）大腸癌研究会 : 遺伝性大腸癌診療ガイドライン2012 年版．東京: 金原出版，2012 ：33–67. 23）Hitchins MP, Wong JJ, Suthers G, et al.: Inheritance of a cancer-associated MLH1 germline epimutation. N Engl J Med 2007 ; 356 : 697–705. 4）Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993 ; 75 : 1215–1225. 11）Cunningham JM, Christensen ER, Tester DJ, et al.: Hypermethylation of hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998 ; 58 : 3455–3460. 26）Crépin M, Dieu MC, Lejeune S, et al.: Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum Mutat 2012 ; 33 : 180–188. 1）Lynch HT, de la Chapelle A : Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999 ; 36 : 801–818. 6）Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 1994 ; 263 : 1625–1629. 16）Gazzoli I, Loda M, Garber J, et al.: A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instabilityhigh tumor. Cancer Res 2002 ; 62 : 3925–3928. 7）Aaltonen LA, Peltomaki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 1993 ; 260 : 812–816. 37）Vasen HFA, Möslein G, Alonso A, et al.: Guidelines for the clinical management of Lynch syndrome（hereditary non-polyposis cancer）. J Med Genet 2007 ; 44 : 353–362. 12）Herman JG, Umar A, Polyak K, et al.: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998 ; 95 : 6870–6875. 24）Morak M, Schackert HK, Rahner N, et al.: Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur J Hum Genet 2008 ; 16 : 804–811. 21）Vasen HF : Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol 2000 ; 18 : 81S–92S. 9）Kim H, Jen J, Vogelstein B, et al.: Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994 ; 145 : 148–156. 17）Miyakura Y, Sugano K, Akasu T, et al.: Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin Gastroenterol Hepatol 2004 ; 2 : 147–156. 34）Ligtenberg MJ, Kuiper RP, Chan TL, et al.: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 30 exons of TACSTD1. Nat Genet 2009 ; 41 : 112–117. |
| References_xml | – reference: 32）Holliday R: The inheritance of epigenetic defects. Science 1987 ; 238 : 163–170. – reference: 15）Young J, Simms LA, Biden KG, et al.: Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 2001 ; 159 : 2107–2116. – reference: 12）Herman JG, Umar A, Polyak K, et al.: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998 ; 95 : 6870–6875. – reference: 9）Kim H, Jen J, Vogelstein B, et al.: Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994 ; 145 : 148–156. – reference: 25）Hitchins MP, Rapkins RW, Kwok CT, et al.: Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5 ′UTR. Cancer Cell 2011 ; 20 : 200–213. – reference: 28）Niessen RC, Hofstra RM, Westers H, et al.: Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 2009 ; 48 : 737–744. – reference: 29）Goel A, Nguyen TP, Leung HC, et al.: De novo constitutional MLH1 epimutations confer earlyonset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer 2011 ; 128 : 869–878. – reference: 11）Cunningham JM, Christensen ER, Tester DJ, et al.: Hypermethylation of hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998 ; 58 : 3455–3460. – reference: 13）Miyakura Y, Sugano K, Konishi F, et al.: Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology 2001 ; 121 : 1300–1309. – reference: 14）Miyakura Y, Sugano K, Konishi F, et al.: Methylation profile of the MLH1 promoter region and their relationship to colorectal carcinogenesis. Genes Chromosomes Cancer 2003 ; 36 : 17–25. – reference: 27）Case AS, Zighelboim I, Mutch DG, et al.: Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. Gynecol Oncol 2008 ; 108 : 438–444. – reference: 30）Hitchins MP, Owens SE, Kwok CT, et al.: Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort. Clin Genet 2011 ; 80 : 428–434. – reference: 33）Chan TL, Yuen ST, Kong CK, et al.: Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 2006 ; 38 : 1178–1183. – reference: 7）Aaltonen LA, Peltomaki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 1993 ; 260 : 812–816. – reference: 3）Fishel R, Lescoe MK, Rao MR, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993 ; 75 : 1027–1038. – reference: 10）Kane MF, Loda M, Gaida GM, et al.: Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997 ; 57 : 808–811. – reference: 19）Hitchins M, Williams R, Cheong K, et al.: MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 2005 ; 129 : 1392–1399. – reference: 20）Valle L, Carbonell P, Fernandez V, et al.: MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin Genet 2007 ; 71 : 232–237. – reference: 17）Miyakura Y, Sugano K, Akasu T, et al.: Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin Gastroenterol Hepatol 2004 ; 2 : 147–156. – reference: 21）Vasen HF : Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol 2000 ; 18 : 81S–92S. – reference: 35）Ligtenberg MJ, Kuiper RP, Geurts van Kessel A, Hoogerbrugge N : EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam Cancer 2013 ; 12 : 169–174. – reference: 34）Ligtenberg MJ, Kuiper RP, Chan TL, et al.: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 30 exons of TACSTD1. Nat Genet 2009 ; 41 : 112–117. – reference: 36）Koinuma K, Shitoh K, Miyakura Y, et al.: Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 2004 ; 108 : 237–242. – reference: 18）Suter CM, Martin DI, Ward RL : Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 2004 ; 36 : 497–501. – reference: 6）Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 1994 ; 263 : 1625–1629. – reference: 1）Lynch HT, de la Chapelle A : Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999 ; 36 : 801–818. – reference: 24）Morak M, Schackert HK, Rahner N, et al.: Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur J Hum Genet 2008 ; 16 : 804–811. – reference: 22）大腸癌研究会 : 遺伝性大腸癌診療ガイドライン2012 年版．東京: 金原出版，2012 ：33–67. – reference: 31）Ward RL, Dobbins T, Lindor NM, et al.: Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet Med 2013 ; 15 : 25–35. – reference: 2）Lynch HT, Lynch PM, Lanspa SJ, et al.: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009 ; 76 : 1–18. – reference: 37）Vasen HFA, Möslein G, Alonso A, et al.: Guidelines for the clinical management of Lynch syndrome（hereditary non-polyposis cancer）. J Med Genet 2007 ; 44 : 353–362. – reference: 5）Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994 ; 368 : 258–261. – reference: 38）Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer（Lynch Syndrome） and Microsatellite Instability. J Natl Cancer Inst 2004; 96: 261–268. – reference: 4）Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993 ; 75 : 1215–1225. – reference: 16）Gazzoli I, Loda M, Garber J, et al.: A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instabilityhigh tumor. Cancer Res 2002 ; 62 : 3925–3928. – reference: 23）Hitchins MP, Wong JJ, Suthers G, et al.: Inheritance of a cancer-associated MLH1 germline epimutation. N Engl J Med 2007 ; 356 : 697–705. – reference: 8）Thibodeau SN, Bren G, Schaid D : Microsatellite instability in cancer of the proximal colon. Science 1993 ; 260 : 816–819. – reference: 26）Crépin M, Dieu MC, Lejeune S, et al.: Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum Mutat 2012 ; 33 : 180–188. |
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| Snippet | MLH1 epimutation は，生殖細胞系列にMLH1 遺伝子のプロモーター領域のメチル化を認め，若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候... MLH1 epimutationは, 生殖細胞系列にMLH1遺伝子のプロモーター領域のメチル化を認め, 若年のうちに大腸癌をはじめとするリンチ症候群関連腫瘍を多発する非常に稀な症候... |
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| Title | MLH1 epimutationの現状 |
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| ispartofPNX | 家族性腫瘍, 2014, Vol.14(2), pp.29-34 |
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