Skip to main content

Klinik und Genetik des familiären Darmkrebses

Clinical findings and genetics of familial colorectal cancer

Zusammenfassung

Eine familiäre Häufung von Dickdarmkrebs (CRC) und ein früher Erkrankungsbeginn sind Hinweise auf erbliche Tumorsyndrome, die für etwa 3–5% aller CRC verantwortlich sind. Bei diesen monogenen Dispositionen wird der erbliche Dickdarmkrebs ohne Polyposis (HNPCC/Lynch-Syndrom) von der Gruppe der gastrointestinalen Polyposis-Syndrome unterschieden. Bei vielen hereditären Formen besteht ein z. T. charakteristisches Spektrum extrakolonischer Tumoren. Die frühe Erkennung und korrekte Einordnung ist wichtig, da effektive Methoden der Vorsorge und Therapie für Betroffene und Risikopersonen bestehen.

Die Initialdiagnostik umfasst das endoskopische Bild und den histologischen Befund, ergänzt um extraintestinale Manifestationen und die Familienanamnese. Die molekulargenetische Abklärung erfolgt nach weitgehend etablierten und standardisierten Algorithmen. Differenzialdiagnostische Probleme bereiten insbesondere Patienten mit wenigen kolorektalen Adenomen sowie phänotypische Überlappungen bei hamartomatösen Polyposis-Syndromen. Für HNPCC und häufige Polyposis-Syndrome existieren etablierte risikoadaptierte Früherkennungsprogramme.

Der außerhalb der etablierten Tumorsyndrome beobachteten familiären Häufung des – oft spätmanifesten – CRC und dem Auftreten weniger Adenome liegt vermutlich eine multifaktorielle Ätiologie zugrunde. Die Aufklärung der genetischen Faktoren und das Verständnis der beteiligten Signalwege steht hier noch am Anfang, macht aber durch die rasanten methodischen Entwicklungen (z. B. genomweite Assoziationsstudien, CNV-Analysen) rasche Fortschritte.

Abstract

Familial clustering of colorectal cancer (CRC) and early disease onset are indicators of an inherited tumour syndrome. Monogenic dispositions account for 3–5% of all CRC cases and are subdivided into hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome) and various gastrointestinal polyposis syndromes. Many of these syndromes are characterised by a broad spectrum of extracolonic tumours. Early detection and accurate classification are essential in providing effective surveillance and treatment.

Initial diagnosis is based on endoscopic and histological findings as well as on the presence of extracolonic manifestations and family history. Molecular genetic examination is important for the differential diagnosis, evaluation of recurrence risk, and predictive testing of asymptomatic at risk individuals; it is performed according to largely standardised algorithms. Diagnostic difficulties are common among the hamartomatous polyposes due to their broad phenotypic overlap and frequent uncertainties in histological evaluation, as well as among patients with few adenomas. Risk-adapted surveillance guidelines have been established for HNPCC and for the more frequently observed polyposis syndromes.

Beyond established tumour syndromes, familial clustering of CRC (which is often of late onset) or the occurrence of few adenomas is likely to be based upon a multifactorial (complex) etiology. Although identification of the underlying genetic risk factors and biological pathways is still in the early stages, rapid progress is being made due to methodical developments such as genome-wide association studies and CNV analysis.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5

Literatur

  1. 1.

    Aretz S, Propping P, Noethen M (2006) Indikationen zur molekulargenetischen Diagnostik bei erblichen Krankheiten. Dtsch Arztebl 103:A550–A558

    Google Scholar 

  2. 2.

    Aretz S, Stienen D, Uhlhaas S et al (2007) High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 44:702–709

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Cheadle JP, Sampson JR (2003) Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet 12 Spec No 2:R159–R165

    Article  Google Scholar 

  4. 4.

    Chen HM, Fang JY (2009) Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis 24:865–874

    Article  PubMed  Google Scholar 

  5. 5.

    Easton DF, Eeles RA (2008) Genome-wide association studies in cancer. Hum Mol Genet 17:R109–R115

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Galiatsatos P, Foulkes WD (2006) Familial adenomatous polyposis. Am J Gastroenterol 101:385–398

    Article  PubMed  Google Scholar 

  7. 7.

    Hitchins MP, Ward RL (2009) Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet 46:793–802

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Houlston RS, Webb E, Broderick P et al (2008) Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40:1426–1435

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Jass JR (2008) Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract 204:431–447

    Article  PubMed  Google Scholar 

  10. 10.

    Knudsen AL, Bisgaard ML, Bulow S (2003) Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2:43–55

    Article  PubMed  Google Scholar 

  11. 11.

    Levin B, Lieberman DA, McFarland B et al (2008) Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, The US Multi-Society Task Force on Colorectal Cancer, and The American College of Radiology. Gastroenterology 134:1570–1595

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Lynch HT, Lynch PM, Lanspa SJ et al (2009) Review of the lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76:1–18

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Sampson JR, Jones N (2009) MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol 23:209–218

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Schmiegel W, Reinacher-Schick A, Arnold D et al (2008) Aktualisierte S3-Leitlinie „Kolorektales Karzinom“ 2008. Z Gastroenterol 46:799–840

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Schulmann K, Pox C, Tannapfel A, Schmiegel W (2007) The patient with multiple intestinal polyps. Best Pract Res Clin Gastroenterol 21:409–426

    Article  PubMed  Google Scholar 

  16. 16.

    Shlien A, Malkin D (2009) Copy number variations and cancer. Genome Med 1:62

    Article  PubMed  Google Scholar 

  17. 17.

    Tenesa A, Dunlop MG (2009) New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10:353–358

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Vasen HF, Moslein G, Alonso A et al (2008) Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57:704–713

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Vasen HF, Moslein G, Alonso A et al (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44:353–362

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Vogt S, Jones N, Christian D et al (2009) Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology

  21. 21.

    Watson P, Vasen HF, Mecklin JP et al (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123:444–449

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Ward EM, Wolfsen HC (2002) Review article: the non-inherited gastrointestinal polyposis syndromes. Aliment Pharmacol Ther 16:333–342

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Schreibmann IR, Baker M, Amos C, McGarrity TJ (2005) The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol100:476–490

    Google Scholar 

  24. 24.

    Blumenthal GM, Dennis PA (2008) PTEN hamartoma tumor syndromes. Eur J Hum Genet 16:1289–300

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Vasen HF, Watson P et al (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  CAS  PubMed  Google Scholar 

  26. 26.

    Rodriguez-Bigas MA, Boland CR 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

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Umar A, Boland CR et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96: 261–268

    CAS  PubMed  Google Scholar 

  28. 28.

    Broderick P, Carvajal-Carmona L, Pittman AM et al (2007) A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39:1315–1317

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Jaeger E, Webb E, Howarth K et al (2008) Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40:26–28

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Tenesa A, Farrington SM, Prendergast JG et al (2008) Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40:631–637

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Tomlinson I, Webb E, Carvajal-Carmona L et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39:984–988

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Tomlinson IP, Webb E, Carvajal-Carmona L et al (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40:623–630

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Schmiegel W, Pox C, Adler G et al (2004) S3-Leitlinienkonferenz „Kolorektales Karzinom“ 2004. Z Gastroenterol 42:1129

    Article  CAS  PubMed  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht. Die Autoren werden von der Deutschen Krebshilfe e. V. gefördert.

Author information

Affiliations

Authors

Corresponding author

Correspondence to S. Aretz.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Steinke, V., Vogt, S. & Aretz, S. Klinik und Genetik des familiären Darmkrebses. medgen 22, 265–281 (2010). https://doi.org/10.1007/s11825-010-0226-z

Download citation

Schlüsselwörter

  • Erblicher Darmkrebs
  • HNPCC
  • FAP
  • MAP
  • Polyposis

Keywords

  • Hereditary colorectal cancer
  • HNPCC
  • FAP
  • MAP
  • Polyposis