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
