Colorectal cancer (CRC) is one of the major cancer types in the western world including Sweden. However, known genetic risk factors could only explain a limited part of heritability of the disease. ...Moreover, colon and rectal cancers are habitually discussed as one entity, colorectal cancer, although different carcinogenesis has been recognized. A genome-wide linkage scan in 32 colon- and 56 rectal cancer families from Sweden was performed based on 475 non-FAP/HNPCC patients genotyped using SNP arrays. A maximum HLOD of 2.50 at locus 6p21.1-p12.1 and a HLOD of 2.56 at 18p11.2 was obtained for colon and rectal cancer families, respectively. Exome sequencing over the regions of interest in 12 patients from six families identified 22 and 25 candidate risk variants for colon and rectal cancer, respectively. Haplotype association analysis in the two regions was carried out between additional 477 familial CRC cases and 4780 controls and suggested candidate haplotypes possibly associated with CRC risk. This study suggested two new linkage regions for colon cancer and rectal cancer with candidate predisposing variants. Further studies are required to elucidate the pathogenic mechanism of these regions and to pinpoint the causative genes.
Colorectal cancer (CRC), prostate cancer (PrC), and gastric cancer (GC) are common worldwide, and the incidence is to a certain extent dependent on genetics. We have recently shown that in families ...with more than one case of CRC, the risk of other malignancies is increased. We therefore suggested the presence of not yet described CRC syndromes. In this study, we have searched for genetic susceptibility loci for potential cancer syndromes involving CRC combined with PrC and/or GC. We have performed SNP (single‐nucleotide polymorphism)‐based linkage analyses in 45 families with CRC, PrC, and GC. In the regions with suggested linkage, we performed exome and association haplotype analyses. Five loci generated a high logarithm of odds (HLOD) score >2, suggestive of linkage, in chromosome bands 1q31‐32, 1q24‐25, 6q25‐26, 18p11‐q11, and Xp11. Exome analysis detected no potential pathogenic sequence variants. The haplotype association study showed that one of the top five haplotypes with the lowest P value in the chromosome band 6q25 interestingly was found in the family which contributed the most to the increased HLOD at that locus. This study supports a suggested hereditary cancer syndrome involving CRC and PrC and indicates a location at 6q25. The impact of this locus needs to be confirmed in additional studies.
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.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the ...feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data.
Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks.
The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk.
Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
Most known cancer syndromes confer an increased risk of more than one tumour types, and families with more than one colorectal cancer often segregate other cancers as well. The aim of this study was ...to examine if there is a general increased risk of other cancers in colorectal cancer families, which are defined as having two or more cases of colorectal cancer in close relatives.
The study used a detailed family history of cancer diagnoses in a cohort of more than 3,000 consecutive colorectal cancer cases. A comparison was made between families with sporadic and those with familial colorectal cancer cases. Detailed morphology data were used to find further support for putative syndromes.
There were significantly more non-colorectal cancers in the family history of the familial CRC cases (p<0.001), with significantly more gastric cancers (p<0.001), prostate cancers (p<0.001), urinary bladder cancers (p<0.001) and melanomas (p=0.002), leukaemia/lymphomas (p=0.004), gynaecological cancers (p=0.007) and breast cancers (p=0.023). There was also some support for different morphological profiles for four of the five tested syndromes.
This study found support for a general increased risk of one or more different cancer syndromes involving families with colorectal cancer and other cancers. Further studies will define the different possible syndromes and determine the genetic background.
High-penetrance mutations in a small group of genes have been identified as the causal agent of colorectal cancer (CRC) in
high-risk families. Our understanding of the sporadic cases is, however, ...much more limited and only in the past two years
have multicentric genome-wide association studies (GWAS) started to unravel the complex genetic architecture behind this common
forms. To date, ten loci have been associated with an increased risk of CRC. Environmental factors play a role as well as
other genetic factors yet to be discovered. The search for common variants with a low penetrance has come to an end, at least
in the European population, and the focus now moves to less common variants (with higher penetrance) and to unclassified variants
of unknown significance. As yet, less than 10% of the 35% genetic contribution to CRC is known.
Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. ...A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4,
= 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2,
= 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA,
and
, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in
, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as
or the processed transcript
.
Recent genome-wide association studies have identified multiple genetic loci and single nucleotide polymorphisms (SNPs) associated with either increased or decreased risk of colorectal cancer (CRC). ...In the present study, our objective was to determine whether 11 of the new susceptibility CRC loci are associated with tumor morphology and to confirm these loci as distinct and etiologically different risk factors in the development of CRC. The following clinical and morphological parameters were analyzed in 1572 samples: tumor size, T-stage, lymph node metastases, degree of differentiation, mucin production, Crohn-like peritumoral lymphocytic infiltration, tumor-infiltrating lymphocytes, desmoplastic reaction, necrosis, invasion of blood or lymph vessels, perineural growth, medullary type, budding, and tumor margin. One SNP from each of the 11 loci (rs6983267 on 8q24.21, rs16892766 on 8q23.3, rs719725 on 9p24.1, rs10795668 on 10p14, rs3802842 on 11q23.1, rs4444235 on 14q22.2, rs4779584 on 15q13.3, rs9929218 on 16q22.1, rs4939827 on 18q21.1, rs10411210 on 19q13.11, and rs961253 on 20p12.3) was genotyped for all cases. Odds ratios, 95% confidence intervals, and the corresponding P values were calculated for the 11 SNPs identified above. A cross tabulation between SNPs and morphology was performed. Several loci showed statistically significant associations with specific phenotypes. The findings are consistent with pathogenic variants in several loci that act in distinct CRC and morphogenetic pathways. Further large-scale studies are required to validate these findings.
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.
Recent genome-wide association studies have identified multiple genetic loci and single nucleotide polymorphisms (SNPs) associated with either increased or decreased risk of colorectal cancer (CRC). ...In the present study, our objective was to determine whether 11 of the new susceptibility CRC loci are associated with tumor morphology and to confirm these loci as distinct and etiologically different risk factors in the development of CRC. The following clinical and morphological parameters were analyzed in 1572 samples: tumor size, T-stage, lymph node metastases, degree of differentiation, mucin production, Crohn-like peritumoral lymphocytic infiltration, tumor-infiltrating lymphocytes, desmoplastic reaction, necrosis, invasion of blood or lymph vessels, perineural growth, medullary type, budding, and tumor margin. One SNP from each of the 11 loci (rs6983267 on 8q24.21, rs16892766 on 8q23.3, rs719725 on 9p24.1, rs10795668 on 10p14, rs3802842 on 11q23.1, rs4444235 on 14q22.2, rs4779584 on 15q13.3, rs9929218 on 16q22.1, rs4939827 on 18q21.1, rs10411210 on 19q13.11, and rs961253 on 20p12.3) was genotyped for all cases. Odds ratios, 95% confidence intervals, and the corresponding P values were calculated for the 11 SNPs identified above. A cross tabulation between SNPs and morphology was performed. Several loci showed statistically significant associations with specific phenotypes. The findings are consistent with pathogenic variants in several loci that act in distinct CRC and morphogenetic pathways. Further large-scale studies are required to validate these findings.
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