Skip to main content
SpringerLink
Log in

A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours

  • Short Communication
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

We have previously established in a large retrospective study that testing for microsatellite instability (MSI) in colorectal cancer (CRC) from patients aged <60 years was an effective first screen to identify individuals with Lynch syndrome (LS). From these findings, MSI and/or immunohistochemical (IHC) screening was recommended for all newly diagnosed CRC patients aged <60 years in Western Australia, regardless of family history of cancer. In the current study we evaluated the utility of routine MSI/IHC screening by diagnostic pathology laboratories for the detection of previously undiagnosed individuals and families with LS. From January 2009 to December 2010, 270 tumours were tested for MSI and for expression of MLH1, PMS2, MSH2 and MSH6 using IHC. Cases showing MSI and/or loss of expression were also tested for the BRAF V600E hotspot mutation. Seventy cases were found to have MSI, of which 25 were excluded from further investigation as possible LS cases due to presence of the BRAF V600E mutation. The remaining 45 “red flag” cases were eligible for germline testing based on their MSI, IHC and BRAF status. From 31 cases tested to date, 15 germline mutations have been found. Thirteen were from individuals not previously recognized as LS and two were untested members from known LS families. Extrapolation of the mutation incidence (15/31, 48%) to all red flag cases (n = 45) suggests that approximately 22 mutation carriers exist in this cohort. This value approximates the number of CRC cases due to LS that could be expected to arise in the Western Australian population over a two-year period (n = 24), assuming that 1% of all CRCs are due to LS. Although further improvements in workflow can be made, our preliminary findings following the implementation of state-wide routine MSI and IHC testing in Western Australia indicate that the majority of LS cases are being identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Cunningham J, Kim C, Christensen E, Tester D, Parc Y, Burgart L, Halling K, McDonnell S, Schaid D, Walsh V et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Human Genet 69:780–790

    Article  CAS  Google Scholar 

  2. Katballe N, Christensen M, Wikman F, Ørntoft F, Laurberg S (2002) Frequency of hereditary nonpolyposis colorectal cancer in Danish colorectal cancer patients. Gut 50:43–51

    Article  PubMed  CAS  Google Scholar 

  3. Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, Xicola R, Rodriguez-Moranta F, Paya A, Jover R et al (2005) Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. J Am Med Assoc 293:1986–1994

    Article  CAS  Google Scholar 

  4. Aaltonen L, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomäki P, Chadwick R, Kääriäinen H, Eskelinen M, Järvinen H et al (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Eng J Med 338:1481–1487

    Article  CAS  Google Scholar 

  5. Vasen H, Taal B, Nagengast F, Griffioen G, Menko F, Kleibeuker J, Offerhaus G, Meera Khan P (1995) Hereditary non-polyposis colorectal cancer: results of long-term surveillance in 50 families. Eur J Cancer 31A(7–8):1145–1148

    Article  PubMed  CAS  Google Scholar 

  6. Järvinen H, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen L, Peltomäki P, Chapelle ADL, Mecklin J (2000) Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829–834

    Article  PubMed  Google Scholar 

  7. Vasen H, Watson P, Mecklin J, Lynch H (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the international collaborative group on HNPCC. Gastroenterology 116:1453–1456

    Article  PubMed  CAS  Google Scholar 

  8. Umar A, Boland C, Terdiman J, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor N, Burgart L, Hamelin R et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Nat Cancer Inst 96:261–268

    Article  PubMed  CAS  Google Scholar 

  9. Lynch H, Riley B, Weismann S, Coronel S, Kinarsky Y, Lynch J, Shaw T, Rubinstein W (2004) Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 100:53–64

    Article  PubMed  Google Scholar 

  10. Kievit W, de Bruin J, Adang E, Ligtenberg M, Nagengasi F, van Krieken J, Hoogerbrugge N (2004) Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate: A meta-analysis. Clin Genet 65:308–316

    Article  PubMed  CAS  Google Scholar 

  11. Terdiman J (2005) It is time to get serious about diagnosing Lynch syndrome (hereditary nonpolyposis colorectal cancer with defective DNA mismatch repair) in the general population. Gastroenterology 129:741–744

    PubMed  Google Scholar 

  12. Schofield L, Watson N, Grieu F, Li W, Zeps N, Harvey J, Stewart C, Abdo M, Goldblatt J, Iacopetta B (2009) Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer 124:1097–1102

    Article  PubMed  CAS  Google Scholar 

  13. Deng G, Bell I, Crawley S, Gum J, Terdiman J, Allen B, Truta B, Sleisenger M, Kim Y (2004) BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10:191–195

    Article  PubMed  CAS  Google Scholar 

  14. Domingo E, Laiho P, Ollikäinen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espín E, Armengol M et al (2004) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 4:664–668

    Article  Google Scholar 

  15. Percesepe A, Borghi F, Menigatti M, Losi L, Foroni M, Di Gregorio C, Rossi G, Pedroni M, Sala E, Vaccina F et al (2001) Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study. J Clin Oncol 19:3944–3950

    PubMed  CAS  Google Scholar 

  16. Samowitz W, Curtin K, Lin H, Robertson M, Schaffer D, Nichols M, Gruenthal K, Leppert M, Slattery M (2001) The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121:830–838

    Article  PubMed  CAS  Google Scholar 

  17. Threlfall T, Thompson J (2010) Cancer incidence and mortality in Western Australia 2008: Department of Health, Perth, Western Australia (ISSN:0816-2999). Statistical Series number 87 (http://www.health.wa.gov.au/wact/)

  18. Watson N, Grieu F, Morris M, Harvey J, Stewart C, Schofield L, Goldblatt J, Iacopetta B (2007) Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer. J Mol Diagn 9:472–478

    Article  PubMed  CAS  Google Scholar 

  19. Li W, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B (2006) BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer 5:2

    Article  PubMed  Google Scholar 

  20. Canard G, Lefevre H, Colas C, Coulet F, Svrcek M, Lascols O, Hamelin R, shields C, Duval A, Flejou J-F,Soubrier F, Tiret E, Parc Y (2011) Screening for Lynch Syndrome in colorectal cancer: are we doing enough? Ann Surg Oncol (Published online ahead of print) doi:10.1245/s10434-011-2014-7

  21. Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior T, Westman J et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Eng J Med 352:1851–1860

    Article  CAS  Google Scholar 

  22. Salovaara R, Loukola A, Kristo P, Kääriäinen H, Ahtola H, Eskelinen M, Härkőnen N, Julkunen R, Kangas E, Ojala S et al (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18:2193–2200

    PubMed  CAS  Google Scholar 

  23. Muller A, Giuffre G, Edmonston T, Mathiak M, Roggendorf B, Heinmoller E, Brodegger T, Tuccari G, Mangold E, Buettner R et al (2004) Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohistochemistry. J Mol Diagn 6:308–315

    Article  PubMed  Google Scholar 

  24. Overbeek L, Ligtenberg M, Willems R, Hermens R, Blokx W, Dubois S, van der Linden H, Meijer J, Mlynek-Kersjes M, Hoogerbrugge N et al (2008) Interpretation of immunohistochemistry for mismatch repair proteins is only reliable in a specialized setting. Am J Surg Pathol 32:1246–1251

    Article  PubMed  Google Scholar 

  25. Ferreira S, Claro I, Lage P, Filipe B, Fonseca R, Sousa R, Francisco I, Chaves P, Albuquerque C, Leitao C (2008) Colorectal adenomas in young patients: microsatellite instability is not a useful marker to detect new cases of Lynch syndrome. Dis Colon Rectum 51:909–915

    Article  PubMed  Google Scholar 

  26. Stoffel E, Syngal S (2005) Adenomas in young patients: what is the optimal evaluation? Am J Gastroenterology 100:1150–1153

    Article  Google Scholar 

  27. Shia J, Klimstra D, Nafa K, Offit K, Guillem J, Markowitz A, Gerald W, Ellis N (2005) Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol 29:96–104

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the contribution of the laboratory staff, colorectal surgeons, gastroenterologists, WA Cancer Registry staff, clinical geneticists and genetic counsellors who assisted with this project.

Author information

Authors and Affiliations

  1. Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA, Australia

    Lyn Schofield & Jack Goldblatt

  2. School of Surgery, University of Western Australia, Nedlands, WA, Australia

    Lyn Schofield & Barry Iacopetta

  3. School of Paediatrics and Child Health, University of Western Australia, Nedlands, WA, Australia

    Lyn Schofield & Jack Goldblatt

  4. Molecular Pathology, PathWest, Nedlands, WA, Australia

    Fabienne Grieu & Benhur Amanuel

Authors
  1. Lyn Schofield
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabienne Grieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jack Goldblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benhur Amanuel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barry Iacopetta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lyn Schofield.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schofield, L., Grieu, F., Goldblatt, J. et al. A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours. Familial Cancer 11, 1–6 (2012). https://doi.org/10.1007/s10689-011-9494-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-011-9494-2

Keywords

Search

Navigation