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

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Abstract

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.

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Abbreviations

MSI:

Microsatellite instability

IHC:

Immunohistochemistry

AC II:

Amsterdam criteria II

rBG:

Revised Bethesda guidelines

MMR:

Mismatch repair

MLPA:

Multiplex-ligation dependent-probe amplification

FCC-X:

Familial colorectal cancer type-X

HNPCC:

Hereditary nonpolyposis colon cancer

FAP:

Familial adenomatous polyposis

MMR-deficient or-proficient FCC:

Mismatch repair deficient or proficient, familial colorectal cancer

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Acknowledgments

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).

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Authors and Affiliations

  1. Research Group Human Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland

    Michal Kovac, Hansjakob Mueller & Karl Heinimann

  2. Functional Genomics Center, University of Zurich, Zurich, Switzerland

    Endre Laczko

  3. Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland

    Ritva Haider, Josef Jiricny & Giancarlo Marra

Authors
  1. Michal Kovac
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  2. Endre Laczko
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  3. Ritva Haider
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  4. Josef Jiricny
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  5. Hansjakob Mueller
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  6. Karl Heinimann
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  7. Giancarlo Marra
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Correspondence to Karl Heinimann or Giancarlo Marra.

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Kovac, M., Laczko, E., Haider, R. et al. Familial colorectal cancer: eleven years of data from a registry program in Switzerland. Familial Cancer 10, 605–616 (2011). https://doi.org/10.1007/s10689-011-9458-6

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  • DOI: https://doi.org/10.1007/s10689-011-9458-6

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