Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers.
Heritable germline epimutations in MSH2 have been reported in a few Lynch syndrome families that lacked germline mutations in the MSH2 gene. It is not known whether somatic MSH2 methylation occurs in MSH2 mutation-positive Lynch syndrome subjects or sporadic colorectal cancers (CRC). Therefore, we determined the methylation status of the MSH2 gene in 268 CRC tissues, including 222 sporadic CRCs and 46 Lynch syndrome tumors that did not express MSH2. We also looked for microsatellite instability (MSI), germline mutations in the MSH2 and EpCAM genes, somatic mutations in BRAF and KRAS, and the CpG island methylator phenotype (CIMP). We observed that somatic MSH2 hypermethylation was present in 24% (11 of 46) of MSH2-deficient (presumed Lynch syndrome) tumors, whereas no evidence for MSH2 methylation existed in sporadic CRCs (MSI and microsatellite stable) or normal colonic tissues. Seven of 11 (63%) patients with MSH2 methylation harbored simultaneous pathogenic germline mutations in the MSH2 gene. Germline EpCAM deletions were present in three of four patients with MSH2 methylation but without pathogenic MSH2 germline mutations. The mean methylation scores at CIMP-related markers were significantly higher in Lynch syndrome tumors with MSH2 methylation than MSH2-unmethylated CRCs. In conclusion, our data provide evidence for frequent MSH2 hypermethylation in Lynch syndrome tumors with MSH2 deficiency. MSH2 methylation in this subset of individuals is somatic and may serve as the "second hit" at the wild-type allele. High levels of aberrant methylation at CIMP-related markers in MSH2-methylated tumors raise the possibility that MSH2 is a target susceptible to aberrant methylation in Lynch syndrome.
Nagasaka
Takeshi
T
Division of Gastroenterology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas 75246, USA.
Rhees
Jennifer
J
Kloor
Matthias
M
Gebert
Johannes
J
Naomoto
Yoshio
Y
Boland
C Richard
CR
Goel
Ajay
A
D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D018095:Germ-Line Mutation; D006801:Humans; D018895:Microsatellite Repeats; D008957:Models, Genetic; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
Hum Mutat. 1997;10(2):89-99
9259192
Gastroenterology. 2008 Jun;134(7):1950-60, 1960.e1
18435933
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8681-6
10411935
Oncogene. 2002 Oct 24;21(49):7585-92
12386821
Hum Genet. 1997 Nov;101(1):51-5
9385369
Adv Cancer Res. 1997;71:93-119
9111864
J Clin Oncol. 2004 Nov 15;22(22):4584-94
15542810
Cancer Res. 1993 Dec 15;53(24):5853-5
8261393
Nat Genet. 1995 Jan;9(1):48-55
7704024
Science. 1993 May 7;260(5109):812-6
8484121
Nat Genet. 2009 Jan;41(1):112-7
19098912
Cancer Res. 1998 Nov 15;58(22):5248-57
9823339
Int J Cancer. 2005 Sep 20;116(5):692-702
15849733
N Engl J Med. 2003 Mar 6;348(10):919-32
12621137
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5
9618505
Nat Genet. 2006 Oct;38(10):1178-83
16951683
N Engl J Med. 2007 Feb 15;356(7):697-705
17301300
Hum Mutat. 2009 Feb;30(2):197-203
19177550
Nat Genet. 2004 May;36(5):497-501
15064764
Gastroenterology. 2007 Jan;132(1):127-38
17087942
Cell. 1993 Dec 17;75(6):1215-25
8261515
Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
12202775
Cancer Res. 1997 Mar 1;57(5):808-11
9041175
J Clin Oncol. 2006 Sep 10;24(26):4285-92
16908935
Nature. 1994 Sep 1;371(6492):75-80
8072530
Cancer Res. 2002 Jul 15;62(14):3925-8
12124320
Genes Chromosomes Cancer. 2009 Aug;48(8):737-44
19455606
Int J Cancer. 2007 May 1;120(9):1922-9
17278092
Nat Genet. 2007 May;39(5):573; author reply 576
17460681