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The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24

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Abstract

Hereditary colorectal cancer accounts for approximately 30 % of all colorectal cancers, but currently only 5 % of these families can be explained by highly penetrant, inherited mutations. In the remaining 25 % it is not possible to perform a gene test to identify the family members who would benefit from prophylactic screening. Consequently, all family members are asked to follow a screening program. The purpose of this study was to localize a new gene which causes colorectal cancer. We performed a linkage analysis using data from a SNP6.0 chip in one large family with 12 affected family members. We extended the linkage analysis with microsatellites (STS) and single nucleotide polymorphisms (SNP’s) and looked for the loss of heterozygosity in tumour tissue. Furthermore, we performed the exome sequencing of one family member and we sequenced candidate genes by use of direct sequencing. Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results.

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Abbreviations

CRC:

Colorectal cancer

DNA:

Deoxyribonucleic acid

FAP:

Familial adenomatous polyposis

HNPCC:

Hereditary non-polyposis colorectal cancer

LOD score:

Logarithm of the odds score

LOH:

Loss of heterozygosity

MMR genes:

Mismatch repair genes

PCR:

Polymerase chain reaction

SNP:

Single nucleotide polymorphism

STS-markers:

Sequence-tagged sites

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Acknowledgments

We would like to thank Annemette Friis Mikkelsen, Ha Thi Cam Nguyen, Hanne Hadberg and Pernille Froh for their skilled laboratory work, Lone Sunde for karyotyping, and Mads Bak and Yuan Mang for exome their sequencing and bioinformatics. Rhonwyn Bisgaard is thanked for linguistic support. The work was supported financially by the “Danish Cancer Society”, “Else og Mogens Wedell-Wedellsborgs Fond” and "Nordic Cancer Union".

Conflict of interest

None.

Ethical standard

The study was approved by the Danish Data Protection Agency (J. nr. 2013-54-0582), was performed on individuals who had given their oral and written consent and was carried out in accordance with the ethical standards laid down in the Declaration of Helsinki.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Faculty of Health, Panum Institute 24.4, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark

    Laura Aviaja Rudkjøbing, Hans Eiberg, Marie Louise Mølgaard Binderup & Marie Luise Bisgaard

  2. Department of Cellular and Molecular Medicine, Faculty of Health, Panum Institute 22.4, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark

    Hanne Birte Mikkelsen

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  1. Laura Aviaja Rudkjøbing
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Correspondence to Marie Luise Bisgaard.

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Rudkjøbing, L.A., Eiberg, H., Mikkelsen, H.B. et al. The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24. Familial Cancer 14, 393–400 (2015). https://doi.org/10.1007/s10689-015-9791-2

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