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Identifying Lynch Syndrome: We Are All Responsible

  • Original Contribution
  • Published:
Diseases of the Colon & Rectum

Abstract

Purpose

The Amsterdam criteria and Bethesda guidelines are used to identify patients with Lynch syndrome. A family history of Lynch syndrome-related cancers or histopathology suggestive of microsatellite instability should prompt responses by the pathologist and clinician. This study evaluated the impact of microsatellite instability pathology findings on Lynch syndrome evaluation by clinicians.

Methods

Microsatellite unstable tumors were identified from a maintained tissue bank, and MLH1 methylation was determined. Clinical information and management recommendations by the pathologist and clinician were collected from the medical record.

Results

Fifty-one patients with microsatellite unstable colorectal tumors were identified between 2003 and 2006. Thirteen (25 percent) patients were appropriately referred for additional testing, including eight with documented microsatellite instability histology and five based on history alone. Thirty-seven (73 percent) patients with microsatellite unstable tumors were not detected by pathologists or clinicians, and no additional workup for Lynch syndrome was performed. Two patients met Amsterdam criteria and represent potentially missed Lynch syndrome.

Conclusions

Microsatellite instability-H histology was the driving force for the Lynch syndrome evaluation. Histopathology alone failed to identify all potential Lynch syndrome patients. Omission of an adequate familial risk assessment may lead to missed diagnosis of Lynch syndrome when suspicious histopathology fails to trigger appropriate testing.

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References

  1. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998;338:1481–7.

    Article  PubMed  CAS  Google Scholar 

  2. Lamberti C, Mangold E, Pagenstecher C, et al. Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. Digestion 2006;74:58–67.

    Article  PubMed  CAS  Google Scholar 

  3. Pinol V, Castells A, Andreu M, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 2005;293:1986–94.

    Article  PubMed  CAS  Google Scholar 

  4. Aaltonen LA, Peltomaki P, Mecklin JP, et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994;54:1645–8.

    PubMed  CAS  Google Scholar 

  5. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260:812–6.

    Article  PubMed  CAS  Google Scholar 

  6. Schiemann U, Muller-Koch Y, Gross M, et al. Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: genetic reclassification and correlation with clinical features. Digestion 2004;69:166–76.

    Article  PubMed  CAS  Google Scholar 

  7. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003;21:1174–9.

    Article  PubMed  CAS  Google Scholar 

  8. Cunningham JM, Kim CY, Christensen ER, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 2001;69:780–90.

    Article  PubMed  CAS  Google Scholar 

  9. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998;58:1713–8.

    PubMed  CAS  Google Scholar 

  10. Eshleman JR, Markowitz SD. Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 1995;7:83–9.

    Article  PubMed  CAS  Google Scholar 

  11. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816–9.

    Article  PubMed  CAS  Google Scholar 

  12. Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998;58:3455–60.

    PubMed  CAS  Google Scholar 

  13. Menigatti M, Di Gregorio C, Borghi F, et al. Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer. Genes Chromosomes Cancer 2001;31:357–61.

    Article  PubMed  CAS  Google Scholar 

  14. Capel E, Fléjou JF, Hamelin R. Assessment of MLH1 promoter methylation in relation to gene expression requires specific analysis. Oncogene 2007;26:7596–600.

    Article  PubMed  CAS  Google Scholar 

  15. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:424–5.

    Article  PubMed  CAS  Google Scholar 

  16. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–8.

    Article  PubMed  CAS  Google Scholar 

  17. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758–62.

    Article  PubMed  CAS  Google Scholar 

  18. Boland CR, Thibodeau SN, Hamilton SR, et al. 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 1998;58:5248–57.

    PubMed  CAS  Google Scholar 

  19. Jass JR, Smyrk TC, Stewart SM, Lane MR, Lanspa SJ, Lynch HT. Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 1994;14:1631–4.

    PubMed  CAS  Google Scholar 

  20. Jenkins MA, Hayashi S, O’Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007;133:48–56.

    Article  PubMed  CAS  Google Scholar 

  21. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007;50:113–30.

    Article  PubMed  CAS  Google Scholar 

  22. Shashidharan M, Smyrk T, Lin KM, et al. Histologic comparison of hereditary nonpolyposis colorectal cancer associated with MSH2 and MLH1 and colorectal cancer from the general population. Dis Colon Rectum 1999;42:722–6.

    Article  PubMed  CAS  Google Scholar 

  23. Yearsley M, Hampel H, Lehman A, Nakagawa H, de la Chapelle A, Frankel WL. Histologic features distinguish microsatellite-high from microsatellite-low and microsatellite-stable colorectal carcinomas, but do not differentiate germline mutations from methylation of the MLH1 promoter. Hum Pathol 2006;37:831–8.

    Article  PubMed  CAS  Google Scholar 

  24. Wolf B, Gruber S, Henglmueller S, Bergmann M, Wrba F, Karner-Hanusch J. Efficiency of the revised Bethesda guidelines (2003) for the detection of mutations in mismatch repair genes in Austrian HNPCC patients. Int J Cancer 2006;118:1465–70.

    Article  PubMed  CAS  Google Scholar 

  25. Lindor NM, Smalley R, Barker M, et al. Ascending the learning curve-MSI testing experience of a six-laboratory consortium. Cancer Biomark 2006;2:5–9.

    PubMed  CAS  Google Scholar 

  26. Trinh BN, Long TI, Laird PW. DNA methylation analysis by MethyLight technology. Methods 2001;25:456–62.

    Article  PubMed  CAS  Google Scholar 

  27. Ogino S, Kawasaki T, Brahmandam M, et al. Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 2006;8:209–17.

    Article  PubMed  CAS  Google Scholar 

  28. Shia J, Klimstra DS, Nafa K, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol 2005;29:96–104.

    Article  PubMed  Google Scholar 

  29. Tanaka J, Watanabe T, Kanazawa T, et al. Left-sided microsatellite unstable colorectal cancers show less frequent methylation of hMLH1 and CpG island methylator phenotype than right-sided ones. J Surg Oncol 2007;96:611–8.

    Article  PubMed  CAS  Google Scholar 

  30. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998;95:6870–5.

    Article  PubMed  CAS  Google Scholar 

  31. Jeong SY, Shin KH, Shin JH, et al. Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers. Dis Colon Rectum 2003;46:1069–77.

    Article  PubMed  Google Scholar 

  32. Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 1996;56:4836–40.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Lisa Krumroy and Sarah Plummer for work in microsatellite instability analysis.

Author information

Authors and Affiliations

  1. Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA

    Julian A. Sanchez M.D., Jon D. Vogel M.D., Matthew F. Kalady M.D. & James M. Church M.D.

  2. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA

    Mary P. Bronner M.D.

  3. Dahl-Chase Pathology Associates, Bangor, Maine, USA

    Marek Skacel M.D.

Authors
  1. Julian A. Sanchez M.D.
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  2. Jon D. Vogel M.D.
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  3. Matthew F. Kalady M.D.
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  4. Mary P. Bronner M.D.
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  5. Marek Skacel M.D.
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  6. James M. Church M.D.
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Corresponding author

Correspondence to James M. Church M.D..

Additional information

Supported by Crile Foundation Fellowship, Cleveland Clinic, Cleveland, Ohio.

Presented at the meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer, La Jolla, California, October 21 to 22, 2007.

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Sanchez, J.A., Vogel, J.D., Kalady, M.F. et al. Identifying Lynch Syndrome: We Are All Responsible. Dis Colon Rectum 51, 1750–1756 (2008). https://doi.org/10.1007/s10350-008-9414-1

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  • DOI: https://doi.org/10.1007/s10350-008-9414-1

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