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Genetic association and linkage studies in colorectal cancer

thesis
posted on 2024-09-03, 01:48 authored by Susanna Von HolstSusanna Von Holst

Colorectal cancer (CRC) is the third most common cancer type in the Western world. Over one million patients are diagnosed worldwide yearly. A family history of CRC is a major risk factor for CRC. The total genetic contribution to disease development is estimated to be 35%. High-risk syndromes caused by known genes such as familial adenomatous polyposis (FAP) and Lynch Syndrome (LS) explain less than 5% of that number. Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. In total, germline mutations in known genes and moderate- and low risk variants are today suggested to explain 10-15% of the total genetic burden. Hence, predisposed genetic factor are still left to be found.

The aim of paper I was to investigate if 11 published loci reported to be associated with an increased or decreased risk of colorectal cancer could be confirmed in a Swedish-based cohort. The cohort was composed of 1786 cases and 1749 controls that were genotyped and analyzed statistically. Genotype– phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumor location, was performed. Of 11 loci, 5 showed statistically significant odds ratios similar to previously published findings. Most of the remaining loci showed similar OR to previous publications. Four statistically significant genotype–phenotype associations were reported.

The aim of paper II was to further study these 11 SNPs and their possible correlation with morphological features in tumors. We analyzed 15 histological features in 1572 CRC cases. Five SNPs showed statistically significant associations with morphological parameters. The parameters were poor differentiation, mucin production, decreased frequency of Crohn-like peritumoral reaction and desmoplastic response.

The aim of paper III was to identify new CRC loci using a genome wide linkage analysis. We used 121 non-FAP/LS colorectal cancer families and genotyped 600 subjects using SNP array chips. No statistically significant result was found. However, suggestive linkage was found in the parametric analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2) and one on 17p13.2 (LOD/HLOD=2.0). Our linkage study adds support for the previously suggested region on chromosome 9 and suggests three additional loci to be involved in colorectal cancer risk.

It is debated whether CRC is a single entity or two different entities, colon- and rectal cancer. Studies have recognized their molecular differences. The aim of paper IV was to identify novel colon- and rectal loci. We performed a genome wide linkage analysis using 32 colon- and 56 rectal cancer families. No LOD or HLOD score above three was observed. However, results close to three could be demonstrated. A maximum HLOD= 2.49 at locus 6p21.1-p12.1 and HLOD= 2.55 at locus 18p11.2 was observed for the colon- and rectal cancer families respectively. Exome sequencing was done, on colon and rectal patients, in these regions of interest. We report 25 variants mutated in family members on chromosome 6 and 27 variants on chromosome 18. Further studies are ongoing to elucidate the importance of these variants.

List of scientific papers

I. von Holst S, Picelli S, Edler D, Lenander C, Dalén J, Hjern F, Lundqvist N, Lindforss U, Påhlman L, Smedh K, Törnqvist A, Holm J, Janson M, Andersson M, Ekelund S, Olsson L, Ghazi S, Papadogiannakis N, Tenesa A, Farrington SM, Campbell H, Dunlop MG, Lindblom A. Association studies on 11 published colorectal cancer risk loci. Br J Cancer. 2010 Aug 10;103(4):575-80.
https://doi.org/10.1038/sj.bjc.6605774

II. Ghazi S, von Holst S, Picelli S, Lindforss U, Tenesa A, Farrington SM, Campbell H, Dunlop MG, Papadogiannakis N, Lindblom A; Low-Risk Colorectal Cancer Study Group. Colorectal cancer susceptibility loci in a population-based study: Associations with morphological parameters. Am J Pathol. 2010 Dec;177(6):2688-93.
https://doi.org/10.2353/ajpath.2010.100298

III. Kontham V, von Holst S, Lindblom A. Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden. PLoS One. 2013 Dec 11;8(12):e83936.
https://doi.org/10.1371/journal.pone.0083936

IV. von Holst S, Kontham V, Thutkawkorapin J, Nilsson D and Lindblom A. Linkage analysis in familial colon- and rectal cancer. [Manuscript]

History

Defence date

2014-11-14

Department

  • Department of Molecular Medicine and Surgery

Publisher/Institution

Karolinska Institutet

Main supervisor

Lindblom, Annika

Publication year

2014

Thesis type

  • Doctoral thesis

ISBN

978-91-7549-677-1

Number of supporting papers

4

Language

  • eng

Original publication date

2014-10-23

Author name in thesis

Holst, Susanna von

Original department name

Department of Molecular Medicine and Surgery

Place of publication

Stockholm

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