Advertisement

Somatic Mutations in MLH1 and MSH2 Are a Frequent Cause of Mismatch-Repair Deficiency in Lynch Syndrome-Like Tumors

Published:December 11, 2013DOI:https://doi.org/10.1053/j.gastro.2013.12.002
      Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes. Tumors are characterized by microsatellite instability (MSI). However, a considerable number of MSI-positive tumors have no known molecular mechanism of development. By using Sanger and ion semiconductor sequencing, 25 MSI-positive tumors were screened for somatic mutations and loss of heterozygosity in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutations in these genes. We conclude that 2 acquired events explain the MMR-deficiency in more than 50% of the MMR-deficient tumors without causal germline mutations or promoter methylation.

      Keywords

      Abbreviations used in this paper:

      CRC (colorectal cancer), EC (endometrial cancer), LOH (loss of heterozygosity), MMR (mismatch repair), MSI (microsatellite instability), PCR (polymerase chain reaction)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lynch H.T.
        • et al.
        Clin Genet. 2009; 76: 1-18
        • Hampel H.
        • et al.
        J Clin Oncol. 2008; 26: 5783-5788
        • Watson P.
        • et al.
        Int J Cancer. 2008; 123: 444-449
        • Vasen H.F.
        • et al.
        Gut. 2013; 62: 812-823
        • Kakar S.
        • et al.
        Cancer. 2003; 97: 1421-1427
        • Sourrouille I.
        • et al.
        Fam Cancer. 2013; 12: 27-33
        • Zhang R.
        • Qin W.
        • et al.
        Colorectal Dis. 2012; 14: e80-e89
        • Overbeek L.I.
        • et al.
        Br J Cancer. 2007; 96: 1605-1612
        • Rodríguez-Soler M.
        • et al.
        Gastroenterology. 2013; 144: 926-932
        • Rhees J.
        • et al.
        Fam Cancer. 2013; ([Epub ahead of print])
        • Diouf B.
        • et al.
        Nat Med. 2011; 17: 1298-1303
        • Li F.
        • et al.
        Cell. 2013; 153: 590-600
        • Plon S.E.
        • Eccles D.M.
        • et al.
        Hum Mutat. 2008; 29: 1282-1291
        • Thompson B.A.
        • et al.
        Hum Mutat. 2013; 34: 200-209
      1. ACGS/VKGL Guidelines on evaluation and reporting of sequence variants 2013. Available at: http://www.acgs.uk.com.

      References

        • Overbeek L.I.
        • et al.
        Br J Cancer. 2007; 96: 1605-1612
        • Ligtenberg M.J.
        • Kuiper R.P.
        • Chan T.L.
        • et al.
        Nat Genet. 2009; 41: 112-117
        • Vaughn C.P.
        • et al.
        Hum Mutat. 2010; 31: 588-593
        • Vaughn C.P.
        • et al.
        Hum Mutat. 2011; 32: 1063-1071
        • Tavtigian S.V.
        • et al.
        J Med Genet. 2006; 43: 295-305
        • Adzhubei I.A.
        • Schmidt S.
        • Peshkin L.
        • et al.
        Nat Methods. 2010; 7: 248-249
        • Kumar P.
        • et al.
        Nat Protoc. 2009; 4: 1073-1081
        • Shapiro M.B.
        • et al.
        Nucleic Acids Res. 1987; 15: 7155-7174
        • Yeo G.
        • et al.
        J Comput Biol. 2004; 11: 377-394
        • Reese M.G.
        • et al.
        J Comput Biol. 1997; 4: 311-323
        • Desmet F.O.
        • et al.
        Nucleic Acids Res. 2009; 37: e67
        • Plon S.E.
        • Eccles D.M.
        • et al.
        Hum Mutat. 2008; 29: 1282-1291
        • Thompson B.A.
        • et al.
        Hum Mutat. 2013; 34: 200-209
      1. ACGS/VKGL Guidelines on evaluation and reporting of sequence variants 2013. Available at: http://www.acgs.uk.com.

        • Hütter P.
        • et al.
        J Med Genet. 2002; 39: 323-327
        • Ellison A.R.
        • et al.
        Nucleic Acids Res. 2004; 32: 5321-5338
        • Fan Y.
        • et al.
        Clin Cancer Res. 2007; 32: 7515-7521
        • Thompson B.A.
        • et al.
        Hum Mutat. 2013; 34: 255-265
        • Aronshtam A.
        • et al.
        Nucleic Acids Res. 1996; 24: 2498-2504
        • Alemayehu A.
        • et al.
        Gen Chrom Can. 2008; 47: 906-914
        • Froggatt N.J.
        • et al.
        J Med Genet. 1996; 33: 726-730
        • Raevaara T.E.
        • et al.
        Gastroenterology. 2005; 129: 537-549
        • Hardt K.
        • et al.
        Fam Cancer. 2011; 10: 273-284
        • Shimodaira H.
        • et al.
        Nat Genet. 1998; 19: 384-389
        • Takahashi M.
        • et al.
        Cancer Res. 2007; 67: 4595-4604
      2. MMR Gene Unclassified Gene Database. University of Groningen, The Netherlands. http://www.mmruv.info/.