Skip to main content
SpringerLink
Log in

Molekularpathologische Diagnostik beim erblichen Dickdarmkarzinom

Empfehlungen und Resultate aus dem Verbundprojekt der Deutschen Krebshilfe „Krebsvorsorge und Krebsfrüherkennung bei Familiärem Darmkrebs“

Molecular pathology in hereditary colorectal cancer

Recommendations of the Collaborative German Study Group on Hereditary Colorectal Cancer funded by the German Cancer Aid (Deutsche Krebshilfe)

  • Übersichten
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Zwillingsanalysen legen für etwa 35% der kolorektalen Karzinome (CRC) einen familiären Hintergrund nahe, derzeit sind jedoch die molekularen Grundlagen nur bei etwa 5–10% der Fälle weitergehend aufgeklärt. Diese im engeren Sinne „erblichen“ Formen des CRC sind durch syndromal gehäufte syn- oder metachrone Tumoren beim betroffenen Patienten und seiner Familie gekennzeichnet. Dabei können eine Reihe besonderer histopathologischer Befunde erhoben werden. Grundsätzlich ist zwischen Karzinomsyndromen mit Ausbildung von adenomatösen und relativ seltenen nicht-adenomatösen (hamartomatösen) Polypen zu unterscheiden. Bereits das Patientenalter kann dem Pathologen einen ersten Hinweis auf Erblichkeit geben. Die Stufendiagnostik umfasst zunächst die Tumoranalyse auf Mikrosatelliteninstabilität (MSI) mit ggf. auch vorgeschaltetem immunhistochemischem Nachweis des für MSI ursächlichen Reparaturgenverlustes (MSH2, MSH6; MLH1, PMS2). Die letzte (dritte) Diagnosestufe zielt auf den Mutationsnachweis im Blut (Keimbahnanalyse). Sie erfordert eine eingehende humangenetische Beratung und schriftliche Einwilligung des Patienten.

Abstract

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5–10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes.

In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare.

The patient’s age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

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

Abb. 1a–d
Abb. 2a–f
Abb. 3a–h
Abb. 4
Abb. 5a–c
Abb. 6a–d
Abb. 7a–c

Literatur

  1. Aaltonen LA (1998) Molecular epidemiology of hereditary nonpolyposis colorectal cancer in Finnland. Rec Res Cancer Res 154:306–311

    CAS  Google Scholar 

  2. Aaltonen LA, Peltomäki P, Mecklin JP et al. (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648

    CAS  PubMed  Google Scholar 

  3. Alexander J, Watanabe T, Wu T-T et al. (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535

    CAS  PubMed  Google Scholar 

  4. Bethesda Guideline Workshop (2003) Revised guidelines for hereditary non-polyposis colorectal cancer and microsatellite instability. Meeting Summary, 3rd „International Workshop on Diagnostic Guidelines for Hereditary Non-Polyposis Colorectal Cancer and Microsatellite Instability“, Bethesda 11.–13.12.2002 (Meeting summary: Umar A et al. JNCI, accepted)

  5. 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 58:5248–5257

    PubMed  Google Scholar 

  6. Cunningham JM, Kim CY, Christensen ER et al. (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69:780–790

    CAS  PubMed  Google Scholar 

  7. Fishel R, Lescoe MK, Rao MRS et al. (1993) The human mutator gene homologue MSH2 and its association with hereditary non-polyposis colon cancer. Cell 75:1027–1038

    CAS  PubMed  Google Scholar 

  8. Friedl W, Caspari R, Sengteller M et al. (2001) Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP Families. Gut 48:515–521

    Article  CAS  PubMed  Google Scholar 

  9. Friedl W, Uhlhaas S, Schulmann K et al. (2002) Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet 111:108–111

    Article  CAS  PubMed  Google Scholar 

  10. Hamilton SR, Aaltonen LA (2000) Pathology and genetics of tumours of the digestive system. WHO, IARC, Lyon

  11. Hartmann A, Zanardo L, Bocker-Edmonston T et al. (2002) Frequent microsatellite instability in sporadic tumors of the upper urinary tract. Cancer Res 62:6796–6802

    CAS  PubMed  Google Scholar 

  12. Heinmoller E, Renke B, Beyser K et al. (2001) Pitfalls in diagnostic molecular pathology—significance of sampling error. Virchows Arch 439:504–511

    PubMed  Google Scholar 

  13. Jass JR, Do KA, Simms LA et al. (1998) Morphology of sporadic colorectal cancer with DNA replication errors. Gut 47:597–602

    Article  Google Scholar 

  14. Lanza G, Gafa R, Maestri I et al. (2002) Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol 15:741–749

    PubMed  Google Scholar 

  15. Lichtenstein P, Holm NV, Verkasalo PK et al. (2000) Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

    CAS  PubMed  Google Scholar 

  16. Lindor NM, Burgart LJ, Leontovich O et al. (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048

    CAS  PubMed  Google Scholar 

  17. Lothe RA, Peltomäki P, Meling Gl et al. (1993) Genomic instability in colorectal cancer: Relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852

    CAS  PubMed  Google Scholar 

  18. Lynch HT, Smyrk T, Lynch JF (1996) Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). Int J Cancer 69:38–43

    Article  CAS  PubMed  Google Scholar 

  19. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. New Engl J Med 348:919–932

    Article  CAS  Google Scholar 

  20. Mathiak M, Rutten A, Mangold E et al. (2002) Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test. Am J Surg Pathos 26:338–343

    Article  Google Scholar 

  21. Müller A, Edmonston TB, Corao DA et al. (2002) Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 62:1014–1019

    PubMed  Google Scholar 

  22. Müller W, Burgart L, Krause-Paulus R et al. and ICG-HNPCC (2001) The reliability of immunohistochemistry as a prescreening method of the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)—Results of an international collaborative study. Familial Cancer 1:87–93

    Article  Google Scholar 

  23. Paraf F, Gilquin M, Longy M et al. (2001) MLH1 and MSH2 protein immunohistochemistry is useful for detection of hereditary non-polyposis colorectal cancer in young patients. Histopathology 39:250–258

    Article  CAS  Google Scholar 

  24. Park JG, Vasen HF, Park YJ et al. (2002) Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. Int J Colorectal Dis 17:109–114

    Article  PubMed  Google Scholar 

  25. Peltomäki P, Vasen HFA and the ICG-HNPCC (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. Gastroenterology 113:1146–1158

    CAS  PubMed  Google Scholar 

  26. Ponds de Leon M, Sassatelli R, Benatti P, Roncucci L (1993) Identification of hereditary nonpolyposis colorectal cancer in the general population: the 6-year experience of a population-based registry. Cancer 71:3493–3501

    PubMed  Google Scholar 

  27. Rodriguez-Bigas MA, Boland R, Hamilton SR et al. (1997) A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762

    CAS  PubMed  Google Scholar 

  28. Rüschoff J, Dietmaier W, Lüttges J et al. (1997) Poorly differentiated colonic adenocarcinoma, medullary type. Clinical, phenotypic, and molecular characteristics. Am J Pathol 150:1815–1825

    CAS  PubMed  Google Scholar 

  29. Smyrk TC, Watson P, Kaul K, Lynch HT (2001) Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal cancer. Cancer 91:2417–2422

    Article  CAS  Google Scholar 

  30. Thibodeau SN, Bren G, Schaid (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819

    PubMed  Google Scholar 

  31. Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA (2001) Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol 8:319–327

    Article  CAS  PubMed  Google Scholar 

  32. Young J, Simms LA, Biden KG et al. (2001) Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 159:2107–2116

    CAS  PubMed  Google Scholar 

  33. Zhou XP, Woodford-Richens K, Lehtonen R et al. (2001) Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 69:704–711

    CAS  PubMed  Google Scholar 

  34. Enholm S, Hienonen T, Suomalainen A et al. (2003) Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Am J Pathol 163:827–832

    Google Scholar 

Download references

Danksagung

Die Autoren danken der Deutschen Krebshilfe für die großzügige Förderung im Rahmen des Verbundprojektes „Krebsvorsorge und Krebsfrüherkennung bei Familiärem Darmkrebs“.

Author information

Authors and Affiliations

  1. Institut für Pathologie, Klinikum Kassel

    J. Rüschoff, B. Roggendorf & A. Müller

  2. Institut für Pathologie an den BG-Kliniken Bergmannsheil, Universitätsklinik, Bochum

    F. Brasch

  3. Institut für Pathologie der Universität Bonn

    M. Mathiak & R. Büttner

  4. Institute für Pathologie und Chirurgische Forschung der Universität Dresden

    D. E. Aust & J. Plaschke

  5. Institut für Pathologie der Universität Düsseldorf

    W. Mueller & C. Poremba

  6. Institut für Pathologie der Universität Heidelberg

    M. Kloor

  7. Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München

    G. Keller

  8. Institut für Pathologie, LMU München

    M. Muders & S. Blasenbreu-Vogt

  9. Institut für Pathologie der Universität Regensburg

    P. Rümmele

  10. Institut für Pathologie, Klinikum Kassel, Moenchebergstraße 41–43, 34125 , Kassel

    J. Rüschoff

Authors
  1. J. Rüschoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Roggendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Brasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Mathiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. E. Aust
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Plaschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Poremba
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Kloor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G. Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Muders
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S. Blasenbreu-Vogt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P. Rümmele
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R. Büttner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Rüschoff.

Additional information

Herrn Prof. Dr. Dr. h.c. R. Fischer in dankbarer Anerkennung seiner Arbeit als Vorsitzender des Medizinischen Beirates der Deutschen Krebshilfe (1990–2003).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rüschoff, J., Roggendorf, B., Brasch, F. et al. Molekularpathologische Diagnostik beim erblichen Dickdarmkarzinom. Pathologe 25, 178–192 (2004). https://doi.org/10.1007/s00292-003-0641-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-003-0641-x

Schlüsselwörter

Keywords

Search

Navigation