Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden

PLoS One. 2013 Dec 11;8(12):e83936. doi: 10.1371/journal.pone.0083936. eCollection 2013.

Abstract

Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Chromosomes, Human, Pair 9 / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis
  • Family
  • Genetic Loci*
  • Humans
  • In Vitro Techniques
  • Lod Score*
  • Male
  • Middle Aged
  • Models, Genetic*
  • Neoplastic Syndromes, Hereditary / genetics*
  • Sweden

Grants and funding

Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (20110483), the Swedish Cancer Society (110439), The Swedish research council (20103543), The Stockholm Cancer Foundation (111232) and Nilsson-Ehle Foundation. The SNP technology platform in Uppsala is supported by Knut & Alice Wallenberg Foundation via the Wallenberg Consortium and Uppsala University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.