Familial Cancer

, Volume 10, Issue 3, pp 605–616 | Cite as

Familial colorectal cancer: eleven years of data from a registry program in Switzerland

  • Michal Kovac
  • Endre Laczko
  • Ritva Haider
  • Josef Jiricny
  • Hansjakob Mueller
  • Karl Heinimann
  • Giancarlo Marra


Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumors.


Colorectum Familial cancer Lynch syndrome Mismatch repair Switzerland 



Microsatellite instability




Amsterdam criteria II


Revised Bethesda guidelines


Mismatch repair


Multiplex-ligation dependent-probe amplification


Familial colorectal cancer type-X


Hereditary nonpolyposis colon cancer


Familial adenomatous polyposis

MMR-deficient or-proficient FCC

Mismatch repair deficient or proficient, familial colorectal cancer



We thank the patients and their families for taking part in this long-term study; Marianne Haeusler, Michele Attenhofer, and Sibylle Bertschin for technical assistance; and Marian Everett Kent for editorial assistance. The study was supported by Swiss National Science Foundation grant no. 31003A-122186 (to Giancarlo Marra, Endre Laczko, and Ritva Haider) and funds from the SNF TANDEM program (to Josef Jiricny and Hansjakob Mueller), Oncosuisse Switzerland (to Karl Heinimann and Michal Kovac), the Krebsliga beider Basel (to Karl Heinimann), and the Krebsliga Zentralschweiz (to Karl Heinimann).

Supplementary material

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Supplementary figure 1 (JPG 881 kb)


  1. 1.
    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 76:1–18PubMedCrossRefGoogle Scholar
  2. 2.
    Marra G, Jiricny J (2005) DNA mismatch repair and colon cancer. In: Nigg E (ed) Genome instability in cancer development (advances in experimental medicine and biology). Springer, Netherlands, pp 85–123CrossRefGoogle Scholar
  3. 3.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRefGoogle Scholar
  4. 4.
    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 58:5248–5257PubMedGoogle Scholar
  5. 5.
    Plasilova M, Zhang J, Okhowat R et al (2006) A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient. Genes Chromosom Cancer 45:1106–1110PubMedCrossRefGoogle Scholar
  6. 6.
    Truninger K, Menigatti M, Luz J et al (2005) Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128:1160–1171PubMedCrossRefGoogle Scholar
  7. 7.
    Marra G, Schär P (1999) Recognition of DNA alterations by the mismatch repair system. Biochem J 338(Pt 1):1–13PubMedCrossRefGoogle Scholar
  8. 8.
    Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249PubMedCrossRefGoogle Scholar
  9. 9.
    Kroonenberg PM, Lombardo R (1999) Nonsymmetric correspondence analysis: a tool for analysing contingency tables with a dependence structure. Multivar Behav Res 34:367–396CrossRefGoogle Scholar
  10. 10.
    ter Braak C (1986) Canonical correspondence analysis: a new eigenvector technique for multivariate direct gradient analysis. Ecology 67:1167–1179CrossRefGoogle Scholar
  11. 11.
    Legendre P, Legendre L (1998) Numerical ecology. Elsevier, AmsterdamGoogle Scholar
  12. 12.
    Lindor NM, Rabe K, Petersen GM et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293:1979–1985PubMedCrossRefGoogle Scholar
  13. 13.
    Abdel-Rahman WM, Peltomaki P (2008) Lynch syndrome and related familial colorectal cancers. Crit Rev Oncog 14:1–22 discussion 23–31PubMedGoogle Scholar
  14. 14.
    Woods MO, Williams P, Careen A et al (2007) A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat 28:669–673PubMedCrossRefGoogle Scholar
  15. 15.
    Fokkema IFAC, den Dunnen JT, Taschner PEM (2005) LOVD: easy creation of a locus-specific sequence variation database using an “LSDB-in-a-Box” approach. Hum Mutat 26:63–68PubMedCrossRefGoogle Scholar
  16. 16.
    Hampel H, Stephens JA, Pukkala E et al (2005) Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129:415–421PubMedGoogle Scholar
  17. 17.
    Jasperson KW, Tuohy TM, Neklason DW et al (2010) Hereditary and familial colon cancer. Gastroenterology 138:2044–2058PubMedCrossRefGoogle Scholar
  18. 18.
    Wijnen JT, Vasen HF, Khan PM et al (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339:511–518PubMedCrossRefGoogle Scholar
  19. 19.
    Genuardi M, Anti M, Capozzi E et al (1998) MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer. Int J Cancer 75:835–839PubMedCrossRefGoogle Scholar
  20. 20.
    Benatti P, Roncucci L, Ganazzi D et al (2001) Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer. Int J Cancer 95:323–328PubMedCrossRefGoogle Scholar
  21. 21.
    Bisgaard ML, Jager AC, Myrhoj T et al (2002) Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. Hum Mutat 20:20–27PubMedCrossRefGoogle Scholar
  22. 22.
    Renkonen E, Zhang Y, Lohi H et al (2003) Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol 21:3629–3637PubMedCrossRefGoogle Scholar
  23. 23.
    Llor X, Pons E, Xicola RM et al (2005) Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 11:7304–7310PubMedCrossRefGoogle Scholar
  24. 24.
    Mueller-Koch Y, Vogelsang H, Kopp R et al (2005) Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54:1733–1740PubMedCrossRefGoogle Scholar
  25. 25.
    Valle L, Perea J, Carbonell P et al (2007) Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol 25:781–786PubMedCrossRefGoogle Scholar
  26. 26.
    Terdiman JP, Gum JR Jr, Conrad PG et al (2001) Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 120:21–30PubMedCrossRefGoogle Scholar
  27. 27.
    Scott RJ, McPhillips M, Meldrum CJ et al (2001) Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68:118–127PubMedCrossRefGoogle Scholar
  28. 28.
    Jass JR, Cottier DS, Jeevaratnam P et al (1995) Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet 346:1200–1201PubMedCrossRefGoogle Scholar
  29. 29.
    Vasen HF, Mecklin JP, Khan PM et al (1991) The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRefGoogle Scholar
  30. 30.
    Marra G, Boland CR (1995) Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87:1114–1125PubMedCrossRefGoogle Scholar
  31. 31.
    Marra G, Jiricny J (2003) Multiple colorectal adenomas: is their number up? N Engl J Med 348:845–847PubMedCrossRefGoogle Scholar
  32. 32.
    Trautmann K, Terdiman JP, French AJ et al (2006) Chromosomal instability in microsatellite-unstable and stable colon cancer. Clin Cancer Res 12:6379–6385PubMedCrossRefGoogle Scholar
  33. 33.
    di Pietro M, Sabates Bellver J, Menigatti M et al (2005) Defective DNA mismatch repair determines a characteristic transcriptional profile in proximal colon cancers. Gastroenterology 129:1047–1059PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Michal Kovac
    • 1
  • Endre Laczko
    • 2
  • Ritva Haider
    • 3
  • Josef Jiricny
    • 3
  • Hansjakob Mueller
    • 1
  • Karl Heinimann
    • 1
  • Giancarlo Marra
    • 3
  1. 1.Research Group Human Genetics, Department of BiomedicineUniversity of BaselBaselSwitzerland
  2. 2.Functional Genomics CenterUniversity of ZurichZurichSwitzerland
  3. 3.Institute of Molecular Cancer ResearchUniversity of ZurichZurichSwitzerland

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