Familial Cancer

, Volume 13, Issue 2, pp 219–225

Inversion of exons 1–7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population

  • Jennifer Rhees
  • Mildred Arnold
  • C. Richard Boland
Original Article

Abstract

Germline mutations in DNA mismatch repair (MMR) genes, such as MSH2, cause Lynch syndrome, an autosomal dominant predisposition to colorectal as well as other cancers. Our research clinic focuses on hereditary colorectal cancer, and over the past 9 years we have identified germline mutations in DNA MMR genes in 101 patients using commercial genetic reference laboratories. We also collected samples from twelve patients with absent MSH2 protein expression and microsatellite instability in tumor tissue, with a family history suggestive of Lynch syndrome, but negative germline test results. The most likely explanation for this set of results is that the germline testing did not detect true germline mutations in these patients. Two of our patients with failed commercial testing were later found to have deletions in the 3′ region of EPCAM, the gene just upstream of MSH2, but no explanation could be found for inactivation of MSH2 in the other ten patients. We used allelic dropout in long PCR to look for potential regions of rearrangement in the MSH2 gene. This method detected a potential rearrangement breakpoint in the same region of MSH2 where one breakpoint of a 10 Mb inversion was reported previously. We tested these ten patients for this inversion. Six of 10 patients had the inversion, indicating the importance of including testing for this inversion in patients suspected of having MSH2-type Lynch syndrome in our population. Additionally, this method could be further developed to look for inversions in other genes where current methods of testing fail to find a causative mutation.

KeyWords

Lynch syndrome Inversion MSH2 Colon cancer 

References

  1. 1.
    Boland CR (2005) Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4(3):211–218. doi:10.1007/s10689-004-4489-x PubMedCrossRefGoogle Scholar
  2. 2.
    Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257PubMedGoogle Scholar
  3. 3.
    Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860. doi:10.1056/NEJMoa043146 PubMedCrossRefGoogle Scholar
  4. 4.
    Gylling A, Ridanpaa M, Vierimaa O et al (2009) Large genomic rearrangements and germline epimutations in Lynch syndrome. Int J Cancer 124(10):2333–2340. doi:10.1002/ijc.24230 PubMedCrossRefGoogle Scholar
  5. 5.
    Lynch HT, Riegert-Johnson DL, Snyder C et al (2011) Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol 106(10):1829–1836. doi:10.1038/ajg.2011.203 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Wagner A, van der Klift H, Franken P et al (2002) A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. Genes Chromosomes Cancer 35(1):49–57. doi:10.1002/gcc.10094 PubMedCrossRefGoogle Scholar
  7. 7.
    Chen JM (2008) The 10-Mb paracentric inversion of chromosome arm 2p in activating MSH2 and causing hereditary nonpolyposis colorectal cancer: re-annotation and mutational mechanisms. Genes Chromosomes Cancer 47(6):543–545. doi:10.1002/gcc.20556 PubMedCrossRefGoogle Scholar
  8. 8.
    Kastrinos F, Steyerberg EW, Mercado R et al (2011) The PREMM(1, 2, 6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 140(1):73–81. doi:10.1053/j.gastro.2010.08.021 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Rodriguez-Soler M, Perez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected Lynch syndrome without germline mutation. Gastroenterology 144(5):926 e1–932 e1. doi:10.1053/j.gastro.2013.01.044 (quiz e13–e14)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Jennifer Rhees
    • 1
    • 2
  • Mildred Arnold
    • 1
    • 2
  • C. Richard Boland
    • 1
    • 2
  1. 1.Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal MedicineBaylor University Medical CenterDallasUSA
  2. 2.Baylor Research Institute and Sammons Cancer CenterBaylor University Medical CenterDallasUSA

Personalised recommendations