Familial Cancer

, Volume 10, Issue 3, pp 605–616

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
Article

DOI: 10.1007/s10689-011-9458-6

Cite this article as:
Kovac, M., Laczko, E., Haider, R. et al. Familial Cancer (2011) 10: 605. doi:10.1007/s10689-011-9458-6

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.

Keywords

ColorectumFamilial cancerLynch syndromeMismatch repairSwitzerland

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

Supplementary material

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Supplementary material 1 (XLS 49 kb)
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Supplementary material 2 (XLS 54 kb)
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Supplementary material 3 (XLS 54 kb)
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Supplementary figure 1 (JPG 881 kb)

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