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1.
J Med Genet ; 43(7): e34, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16816021

ABSTRACT

BACKGROUND: Recently, a functionally defective CHEK2 variant I157T has been proposed to associate with an increased risk of several types of cancer. We investigated the CHEK2 I157T variant for colorectal cancer (CRC) predisposition in a large population based study including a significant number of familial CRC cases. METHODS: We screened the CHEK2 I157T variant in a population based series of 1042 Finnish CRC patients using restriction fragment length polymorphism. Mutation status was studied for correlation with clinical characteristics and family history of CRC and other cancers. RESULTS: The frequency of CHEK2 I157T was significantly higher in CRC patients (7.8%, 76/972) than in healthy population controls (5.3%, 100/1885) (OR = 1.5, 95% CI 1.1 to 2.1, p = 0.008). The significant association of CHEK2 I157T with CRC was observed among patients with (10.4%, 14/135) and without (7.4%, 62/837) a family history of CRC (OR = 2.1, 95% CI 1.1 to 3.7, p = 0.01; OR = 1.4, 95% CI 1.0 to 2.0, p = 0.03; respectively). A trend towards higher variant frequency was also noted among patients with multiple primary tumours and a family history of any cancer. CONCLUSIONS: CHEK2 I157T associates with an increased risk of CRC: the association was observed both among familial and sporadic CRC patients. Furthermore, the higher frequency of I157T among patients with multiple primary tumours as well as those with a family history of any cancer supports a role for CHEK2 I157T as a susceptibility allele for multiple cancer types.


Subject(s)
Colorectal Neoplasms/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Case-Control Studies , Checkpoint Kinase 2 , Finland , Gene Frequency , Genetic Predisposition to Disease , Humans , Polymorphism, Restriction Fragment Length , Risk Assessment
2.
J Med Genet ; 42(9): 694-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16141004

ABSTRACT

BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.


Subject(s)
Carcinoma, Squamous Cell/genetics , Colorectal Neoplasms/genetics , Head and Neck Neoplasms/genetics , Leiomyosarcoma/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Proto-Oncogene Proteins c-mdm2/genetics , Adult , Aged , Cohort Studies , Evaluation Studies as Topic , Female , Humans , Male , Middle Aged , Risk , Uterine Neoplasms/drug therapy
3.
Br J Cancer ; 92(6): 1126-9, 2005 Mar 28.
Article in English | MEDLINE | ID: mdl-15756273

ABSTRACT

Mutations in LKB1 lead to Peutz-Jeghers syndrome (PJS). However, only a subset of PJS patients harbours LKB1 mutations. We performed a mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in 28 LKB1-negative PJS patients. No disease-causing mutations were detected in the studied genes in PJS patients from different European populations.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Vesicular Transport/genetics , Mutation , Nuclear Proteins/genetics , Peutz-Jeghers Syndrome/genetics , Transcription Factors/genetics , DNA Helicases , Humans , Introns , Polymorphism, Genetic
4.
J Am Coll Cardiol ; 37(6): 1516-22, 2001 May.
Article in English | MEDLINE | ID: mdl-11345359

ABSTRACT

OBJECTIVES: Our aim was to study whether an insertion/deletion (I/D) polymorphism in the alpha2B-adrenoceptor gene is associated with the risk for cardiovascular diseases. BACKGROUND: alpha2-adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. The alpha2-adrenoceptor subtype B mediates vasoconstriction in mice. A variant of the human alpha2B-adrenoceptor gene that encodes a D of three residues in an intracellular acidic motif has been shown to confer decreased receptor desensitization. This receptor variant could, therefore, be involved in diseases associated with enhanced vasoconstriction. METHODS: This study was part of a prospective population-based study investigating risk factors for cardiovascular diseases in a cohort of middle-aged men from eastern Finland. Nine hundred twelve men aged 46 to 64 years were followed for an average time of 4.5 years. RESULTS: In this study population, 192 men (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) had a heterozygous genotype. In a Cox model adjusting for other coronary risk factors, men with the D/D genotype had 2.2 times (95% confidence interval: 1.1 to 4.4, p = 0.02) the risk to experience an acute coronary event (n = 15 for D/D, 10 for I/I and 12 for I/D) compared with men carrying either of the other two genotypes. The alpha2B-adrenoceptor genotype was not associated with hypertension in this study population. CONCLUSIONS: The D/D genotype of the alpha2B-adrenoceptor is a novel genetic risk factor for acute coronary events, but not for hypertension.


Subject(s)
Coronary Disease/genetics , Gene Deletion , Genetic Predisposition to Disease/genetics , Mutagenesis, Insertional/genetics , Polymorphism, Genetic/genetics , Receptors, Adrenergic, alpha-2/genetics , Analysis of Variance , Blood Pressure , Coronary Disease/blood , Coronary Disease/classification , Coronary Disease/epidemiology , Finland/epidemiology , Genes, Recessive/genetics , Genetic Carrier Screening , Genotype , Humans , Hypertension/complications , Hypertension/diagnosis , Hypertension/therapy , Male , Middle Aged , Population Surveillance , Proportional Hazards Models , Prospective Studies , Risk Assessment , Risk Factors , Survival Analysis
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