Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer - PubMed (original) (raw)

. 2006 Oct;38(10):1178-83.

doi: 10.1038/ng1866. Epub 2006 Sep 3.

Affiliations

• PMID: 16951683
• DOI: 10.1038/ng1866

Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Tsun Leung Chan et al. Nat Genet. 2006 Oct.

Abstract

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.

PubMed Disclaimer

Comment in

• Heritable germline epimutations in humans.
  Horsthemke B. Horsthemke B. Nat Genet. 2007 May;39(5):573-4; author reply 575-6. doi: 10.1038/ng0507-573b. Nat Genet. 2007. PMID: 17460680 No abstract available.
• Inherited epimutation or a haplotypic basis for the propensity to silence?
  Suter CM, Martin DI. Suter CM, et al. Nat Genet. 2007 May;39(5):573; author reply 576. doi: 10.1038/ng0507-573a. Nat Genet. 2007. PMID: 17460681 No abstract available.
• Heritable germline epimutation is not the same as transgenerational epigenetic inheritance.
  Chong S, Youngson NA, Whitelaw E. Chong S, et al. Nat Genet. 2007 May;39(5):574-5; author reply 575-6. doi: 10.1038/ng0507-574. Nat Genet. 2007. PMID: 17460682 No abstract available.

Similar articles

• Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes.
  Huang RL, Chao CF, Ding DC, Yu CP, Chang CC, Lai HC, Yu MH, Liu HS, Chu TY. Huang RL, et al. Cancer Genet Cytogenet. 2004 Sep;153(2):108-14. doi: 10.1016/j.cancergencyto.2004.01.003. Cancer Genet Cytogenet. 2004. PMID: 15350299
• A novel missense MSH2 gene mutation in a patient of a Korean family with hereditary nonpolyposis colorectal cancer.
  Park SJ, Lee KA, Park TS, Kim NK, Song J, Kim BY, Choi JR. Park SJ, et al. Cancer Genet Cytogenet. 2008 Apr 15;182(2):136-9. doi: 10.1016/j.cancergencyto.2008.01.011. Cancer Genet Cytogenet. 2008. PMID: 18406877
• Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene.
  Banville N, Geraghty R, Fox E, Leahy DT, Green A, Keegan D, Geoghegan J, O'Donoghue D, Hyland J, Sheahan K. Banville N, et al. Hum Pathol. 2006 Nov;37(11):1498-502. doi: 10.1016/j.humpath.2006.06.024. Epub 2006 Sep 25. Hum Pathol. 2006. PMID: 16996571
• Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation.
  Hitchins MP. Hitchins MP. Fam Cancer. 2016 Jul;15(3):413-22. doi: 10.1007/s10689-016-9887-3. Fam Cancer. 2016. PMID: 26886015 Review.
• [Germ-line epimutations and human cancer].
  Wu PY, Fan YM, Wang YP. Wu PY, et al. Ai Zheng. 2009 Dec;28(12):1236-42. doi: 10.5732/cjc.009.10266. Ai Zheng. 2009. PMID: 19958615 Review. Chinese.

Cited by

• Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer.
  Hansmann T, Pliushch G, Leubner M, Kroll P, Endt D, Gehrig A, Preisler-Adams S, Wieacker P, Haaf T. Hansmann T, et al. Hum Mol Genet. 2012 Nov 1;21(21):4669-79. doi: 10.1093/hmg/dds308. Epub 2012 Jul 27. Hum Mol Genet. 2012. PMID: 22843497 Free PMC article.
• The role of epigenetics in Lynch syndrome.
  Hitchins MP. Hitchins MP. Fam Cancer. 2013 Jun;12(2):189-205. doi: 10.1007/s10689-013-9613-3. Fam Cancer. 2013. PMID: 23462881 Review.
• Methylation-Based Therapies for Colorectal Cancer.
  Cervena K, Siskova A, Buchler T, Vodicka P, Vymetalkova V. Cervena K, et al. Cells. 2020 Jun 24;9(6):1540. doi: 10.3390/cells9061540. Cells. 2020. PMID: 32599894 Free PMC article. Review.
• Application of molecular diagnostics for the detection of Lynch syndrome.
  Pino MS, Chung DC. Pino MS, et al. Expert Rev Mol Diagn. 2010 Jul;10(5):651-65. doi: 10.1586/erm.10.45. Expert Rev Mol Diagn. 2010. PMID: 20629513 Free PMC article. Review.
• _Cis_-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases.
  Ruiz de la Cruz M, de la Cruz Montoya AH, Rojas Jiménez EA, Martínez Gregorio H, Díaz Velásquez CE, Paredes de la Vega J, de la Cruz Hernández-Hernández F, Vaca Paniagua F. Ruiz de la Cruz M, et al. Cancers (Basel). 2021 Sep 26;13(19):4807. doi: 10.3390/cancers13194807. Cancers (Basel). 2021. PMID: 34638292 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Nature Publishing Group

• Other Literature Sources

  • H1 Connect
  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • The Weizmann Institute of Science GeneCards and MalaCards databases