[show abstract][hide abstract] ABSTRACT: The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR=1.52; CI=1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI=1.02-1.60) and 1.34 (CI=1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI=0.60-0.97) among colon patients and 0.73 (CI=0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles.
European journal of cancer (Oxford, England: 1990) 02/2010; 46(6):1041-8. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.
Statistical analysis was performed using multipoint parametric and nonparametric linkage.
Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).
The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.
[show abstract][hide abstract] ABSTRACT: Defects of the DNA mismatch repair gene hMLH3 were screened by denaturing high-performance liquid chromatography and sequencing in germinal tissue DNA from patients with spermatogenic arrest, with sequence variations being confirmed in genomic DNA by polymerase chain reaction (PCR) direct sequencing analysis. Four missense (2896T/C, 2531C/T) and eight intronic (IVS9+66G/A) variants were found, with the combination of 2531C/T and IVS9+66G/A being identified only in patients with primary meiotic arrest, thus suggesting that two simultaneous hMLH3 variants might predispose to spermatogenic arrest.
Fertility and sterility 01/2008; 88(6):1681-4. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: We serendipitously identified a single nucleotide polymorphism (SNP), 8636C>A (rs1804197) in the 3'-untranslated region of the adenomatous polyposis coli (APC) gene to be associated with autism spectrum disorder (ASD). In order to gain further evidence for the association between the APC locus and ASD, we genotyped four additional adjacent common SNPs (rs2229992, rs42427, rs459552, and rs465899) in the coding regions within the APC gene in a set of Swedish ASDs and controls. One common haplotype TGAG was found to be associated with ASD after haplotype analysis using both Haploview v3.1.1 (P = 0.006) and COCAPHASE v2.403 (P = 0.030). This result is the first to suggest that the genomic locus at APC is associated with ASD, and that the APC gene itself is a good predisposing candidate to be evaluated in future studies due to its important role in neuronal development and function.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):351-4. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: The estrogen receptor alpha (ESR1) mediates the effect of estrogen in target tissues. Estrogen is important in breast cancer development and several polymorphic variants in the ESR1 gene have been investigated for association with breast cancer. The C975G variant is the most extensively studied and has been suggested to be a risk factor.
The frequency of the C975G variant was investigated in 288 sporadic, 197 low-risk non-BRCA1/2 familial and 191 high-risk non-BRCA1/2 familial breast cancer cases and 653 controls.
There was a lower frequency of the C975G variant in high-risk familial breast cancer cases compared to the controls (18% versus 22%, p=0.046). The odds ratio (OR) for the GG homozygotes was 0.2 (95% CI: 0.06-0.8) compared to the CC homozygotes. No association was seen with sporadic or low-risk familial breast cancer.
The results of this study indicated that the common C975G variant may have an effect on familial breast cancer susceptibility.
Anticancer research 01/2006; 26(4B):3077-81. · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many families experience an apparently inherited increased risk of colorectal cancer (CRC) similar to the known syndromes familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Besides these high-risk syndromes, approximately 10% of all CRC cases come from families with 2 affected 1st-degree relatives, and even 1st-degree relatives to a single case of CRC are at increased risk. Risk subjects from these families frequently show polyps at colonoscopy, which suggests the APC gene as a good candidate susceptibility gene for these attenuated polypotic syndromes. We used the sensitive DHPLC technique to search for possible predisposing germline mutations in the entire APC gene in 91 risk subjects from these high- and low-risk syndromes with unknown predisposing genes. Most exons were also screened for mutations in 96 normal controls and 96 colorectal cancer cases. In our study we probably have identified the most common APC variants in a Swedish population. Among 30 germline variants identified, 1 clearly pathogenic nonsense mutation and 11 putative pathogenic variants (10 missense and one 3' UTR) were found in 20 index patients (22%). Twelve silent as well as 5 intronic variants were considered nonpathogenic. Two of the missense variants found here, E1317Q and D1822V, have previously been related to a difference in risk of colorectal cancer. One variant, 8636C>A, located within the 3' UTR region of the APC gene, was suggested to constitute an additional low risk allele with a similar relative risk as the Jewish I1307K mutation (OR = 1.8; 95% CI, 0.96-3.40). The question of whether all the other variants confer an increased colorectal cancer risk warrants future large association studies.
International Journal of Cancer 08/2004; 110(4):550-7. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Over the last few decades it has become clear that highly penetrant disease genes are responsible for a minor proportion of colorectal cancer cases. Families with hereditary syndromes are today recognized and included in surveillance programs known to reduce morbidity and mortality in colorectal cancer. Colorectal cancer is preventable and screening strategies in whole populations are currently under debate. Colorectal cancer can be considered a complex disease, with a combination of predisposing genetic variants and environmental factors that contribute to the illness as a whole. The progress made in the genome project provides an opportunity to determine such genetic variants and environmental factors. This knowledge can be used to define a subpopulation at increased risk for colorectal cancer. It will be more feasible to design preventive strategies for this subgroup than for a whole population.
[show abstract][hide abstract] ABSTRACT: The CCCTC-binding factor (CTCF), known as a versatile transcription factor and chromatin insulator and to be involved in X inactivation, has also been suggested to be a tumour suppressor on 16q. We investigated 153 patients with familial non-BRCA1/BRCA2 breast cancer for germline mutations in the CTCF gene.
Mutation screening of CTCF was performed by denaturing high-performance liquid chromatography followed by cycle sequencing.
We found two sequence variants, 240G-->A in the 5' untranslated region and 1455C-->T (S388S) in exon 4, in five familial breast cancer cases. Three of these five cases had both variants. Cases and controls showed the same prevalence for the two variants, which were found in linkage disequilibrium in most cases and controls.
The present study suggests that germline mutations in CTCF are not important as a risk factor for breast cancer.
Breast cancer research: BCR 01/2004; 6(3):R187-90. · 5.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly associated with at least three currently known DNA mismatch repair genes: (a) hMSH2; (b) hMLH1; and (c) hMSH6. A majority of HNPCC families has identifiable mutations in hMLH1 and hMSH2. When these mutations cause an inherited risk of colorectal cancer, they are also most often associated with microsatellite instability in the tumors. Recently, hMLH3 was suggested to be causative in HNPCC. We screened 70 index patients suggestive of a genetic predisposition for germ-line mutations in hMLH3 with denaturing high-performance liquid chromatography. One frameshift mutation and 11 missense mutations were identified in 16 index patients (23%). Most families presented evidence against hMLH3 as a high risk factor in familial colorectal cancer, and most of the mutations were found in the low risk patients, suggesting hMLH3 to be a low risk gene for colorectal cancer. We demonstrate in one family that a hMLH3 mutation segregated with disease together with a missense mutation in hMSH2, which makes us hypothesize that these mutations work together in an additive manner and result in an elevated risk of colorectal tumors in the family. None of the tumors with hMLH3 mutations showed microsatellite instability, which demonstrates that hMLH3 does not make its contribution to carcinogenesis through an impaired DNA mismatch repair function.
Cancer Research 05/2003; 63(8):1894-9. · 8.65 Impact Factor